WO2001005813A1 - Promedicaments de pseudomycine - Google Patents

Promedicaments de pseudomycine Download PDF

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Publication number
WO2001005813A1
WO2001005813A1 PCT/US2000/015016 US0015016W WO0105813A1 WO 2001005813 A1 WO2001005813 A1 WO 2001005813A1 US 0015016 W US0015016 W US 0015016W WO 0105813 A1 WO0105813 A1 WO 0105813A1
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Prior art keywords
alkyl
hydrogen
cio
prodrug
alkoxy
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PCT/US2000/015016
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English (en)
Inventor
Shu Hui Chen
Michael John Rodriguez
Xicheng David Sun
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Eli Lilly And Company
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Priority to AU53105/00A priority Critical patent/AU5310500A/en
Priority to JP2001511470A priority patent/JP2003505396A/ja
Priority to BR0013153-9A priority patent/BR0013153A/pt
Priority to EP00938005A priority patent/EP1198470A1/fr
Priority to EA200200161A priority patent/EA200200161A1/ru
Priority to CA002379058A priority patent/CA2379058A1/fr
Priority to MXPA02000315A priority patent/MXPA02000315A/es
Publication of WO2001005813A1 publication Critical patent/WO2001005813A1/fr
Priority to NO20020192A priority patent/NO20020192L/no

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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
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to pseudomycin compounds, in particular, prodrugs of pseudomycin compounds.
  • Pseudomycins are natural products isolated from liquid cultures of Pseudo onas syringae (plant-associated bacterium) and have been shown to have antifungal activities.
  • Pseudo onas syringae plant-associated bacterium
  • Pseudomycins a family of novel peptides from Pseudomonas syringae possessing broad-spectrum antifungal activity, " J . Gen . Microbiology, 137(12), 2857-65 (1991) and US Patent Nos. 5,576,298 and 5,837,685
  • syringae e.g., syringomycins, syringotoxins and syringostatins
  • pseudomycins A-C contain hydroxyaspartic acid, aspartic acid, serine, dehydroaminobutyric acid, lysine and diaminobutyric acid.
  • the peptide moiety for pseudomycins A, A', B, B' , C, C corresponds to L-Ser-D-Dab-L-Asp-L-Lys-L-Dab-L-aThr-Z-Dhb-L- Asp (3-OH) -L-Thr (4-C1) with the terminal carboxyl group closing a macrocyclic ring on the OH group of the N-terminal Ser.
  • the analogs are distinguished by the N-acyl side chain, i.e., pseudomycin A is N-acylated by
  • Pseudomycins are known to have certain adverse biological effects. For example, destruction of the endothelium of the vein, destruction of tissue, inflammation, and local toxicity to host tissues have been observed when pseudomycin is administered intraveneously . Therefore, there is a need to identify compounds within this class that are useful for treating fungal infections without the currently observed adverse side effects.
  • the present invention provides a pseudomycin prodrug represented by the following structure which is useful as an antifungal agent. wherein R is
  • R a and R a' are independently hydrogen or methyl, or either R a or R a' is alkyl amino, taken together with R b or R b' forms a six-membered cycloalkyl ring, a six- membered aromatic ring or a double bond, or taken together with R c forms a six-membered aromatic ring;
  • R b and R b' are independently hydrogen, halogen, or
  • R b or R b' is amino, alkylamino, oc- acetoacetate, methoxy, or hydroxy
  • R c is hydrogen, hydroxy, C1-C 4 alkoxy, hydroxy Ci- C 4 alkoxy, or taken together with R e forms a 6-membered aromatic ring or C 5 -C 6 cycloalkyl ring;
  • R e is hydrogen, or taken together with R f is a six-membered aromatic ring, C 5 -C 14 alkoxy substituted six-membered aromatic ring, or C 5 -C 1 4 alkyl substituted six-membered aromatic ring, and
  • R f is Cg-Cis alkyl, or C 5 -C 11 alkoxy
  • R 1 is a hydrogen, halogen, or Cs-C 8 alkoxy, and m is 1, 2 or 3 ;
  • R k is C 5 -Ci 4 alkoxy
  • R is - (CH 2 )-NR m -(C ⁇ 3 -C 18 alkyl), where R m is H, -CH 3 or
  • R 1 is independently hydrogen, an acyloxymethylene-1, 3- dioxolen-2-one (e.g., compounds 1 (a) depicted below), or an acyloxymethylenecarboxylate (e.g., compounds 1 (b) depicted below)
  • R la is hydrogen, Ci-Cio alkyl, Ci-Cio alkenyl , benzyl, or aryl and R lb is hydrogen or methyl provided that at least one R 1 is an acyloxymethylene- , 3-dioxolen-2-one or an acyloxymethylenecarboxylate; and R 3 are independently -OR 2a , or -N(R 2b ) (R 2c ) , where R 2a and R 2b are independently hydrogen, C ⁇ -C ⁇ 0 alkyl
  • C 3 _C ⁇ cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentylmethylene, methylcyclopentyl, cyclohexyl, etc.
  • hydroxy (Ci-Cio) alkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentylmethylene, methylcyclopentyl, cyclohexyl, etc.
  • R 2b is an alkyl carboxylate residue of an aminoacid alkyl ester (e.g., -CHC0 2 CH 3 , -CH(C0 2 CH 3 )CH(CH 3 ) 2/ -CH (C0 2 CH 3 ) CH (phenyl) , -CH(C0 2 CH 3 )CH 2 OH, -CH (C0 2 CH 3 ) CH 2 (p-hydroxyphenyl) , -CH (CO2CH 3 ) CH 2 SH, -CH (C0 2 CH 3 ) CH 2 (CH 2 ) 3 NH 2 , -CH(C0 2 CH 3 )CH 2 (4- or 5-imidazole) , -CH (C0 2 CH 3 ) CH 2 C0 2 CH 3 , -CH(C0 2 CH 3 )CH 2 C ⁇ 2NH2, and the like), and R 2c is hydrogen or Ci-C ⁇ alkyl; and pharmaceutically acceptable salts and solvates thereof.
  • a pharmaceutical formulation which includes the pseudomycin prodrug described above and a pharmaceutically acceptable carrier.
  • a method for treating an antifungal infection in an animal in need thereof which comprises administering to the animal the pseudomycin prodrug described above .
  • the use of the pseudomycin prodrug described above in the manufacture of a medicament for use in treating an antifungal infection in an animal is also provided.
  • alkyl refers to a hydrocarbon radical of the general formula C n H 2 n+ ⁇ containing from 1 to 30 carbon atoms unless otherwise indicated.
  • the alkane radical may be straight (e.g. methyl, ethyl, propyl, butyl, etc.), branched (e.g., isopropyl, isobutyl, tertiary butyl, neopentyl, etc.), cyclic (e.g., cyclopropyl, cyclobutyl, eye1opentyl, methylcyclopentyl, cyclohexyl, etc.), or multi-cyclic (e.g., bicyclo [2.2.1] heptane, spiro [2.2 ]pentane, etc.).
  • alkane radical may be substituted or unsubstituted.
  • alkyl portion of an alkoxy group, alkanoyl, or alkanoate have the same definition as above.
  • alkenyl refers to an acyclic hydrocarbon containing at least one carbon carbon double bond.
  • the alkene radical may be straight, branched, cyclic, or multi- cyclic.
  • the alkene radical may be substituted or unsubstituted.
  • the alkenyl portion of an alkenoxy, alkenoyl or alkenoate group has the same definition as above.
  • aryl refers to aromatic moieties having single (e.g., phenyl) or fused ring systems (e.g., naphthalene, anthracene, phenanthrene, etc.).
  • the aryl groups may be substituted or unsubstituted.
  • alkyl group allows for substitutents which is a classic alkyl, such as methyl, ethyl, propyl, hexyl, isooctyl, dodecyl, stearyl, etc.
  • group specifically envisions and allows for substitutions on 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.
  • 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, a inoalkylthio, carbamyl, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, and combinations thereof .
  • prodrug refers to a class of drugs which result in pharmacological action due to conversion by metabolic processes within the body (i.e., biotransformation) .
  • the pseudomycin prodrug compounds contain linkers that can be cleaved by esterases in the plasma to produce the active drug.
  • animal refers to humans, companion animals (e.g., dogs, cats and horses), food-source animals (e.g., cows, pigs, sheep and poultry), zoo animals, marine animals, birds and other similar animal species.
  • a prodrug derivative of the pseudomycin natural or semi-synthetic products provide less adverse side effects than the corresponding natural products and maintains in vivo efficacy against C. albican, C. neoformans, and A . fumigatus .
  • the prodrug is produced by acylating at least one of the pendant amino groups attached to the lysine or 2 , 4-diaminobutyric acid peptide units in the pseudomycin cyclopeptide ring system to. form an acyl substituent (s) .
  • the acylating agent is generally a acyloxymethylene-1, 3-dioxolen-2-one or acyloxymethylenecarboxylate acylating compound containing a suitable leaving group such that a carbamate linkage with the pendant amino group on the pseudomycin structure can be formed.
  • suitable leaving groups are well known to those skilled in the art and include groups such as p-nitrophenoxy and N-oxysuccinimide .
  • acyloxymethylene-1, 3-dioxolen-2-one acylating compound may be synthesized using the synthetic route shown in scheme I below. For illustrative purposes, a specific acylating compound is depicted. However, it will be understood by those skilled in the art that one could synthesize a variety of derivatives using the same basic synthetic method.
  • acyloxymethylenecarboxylate acylating compound may be synthesized using the synthetic route shown in scheme II below. For illustrative purposes, a specific acylating compound is depicted. However, it will be understood by those skilled in the art that one could synthesize a variety of derivatives using the same basic synthetic method.
  • pseudomycins are natural products isolated from the bacterium Pseudomonas syringae that have been characterized as lipodepsinonapetpides containing a cyclic peptide portion closed by a lactone bond and including the unusual amino acids 4-chlorothreonine (ClThr) , 3-hydroxyaspartic acid (HOAsp) , 2 , 3-dehydro-2-aminobutyric acid (Dhb) , and 2 , 4-diaminobutyric acid (Dab).
  • Isolated strains of P. syringae that produce one or more pseudomycins are known in the art. Wild type strain MSU 174 and a mutant of this strain generated by transposon mutagenesis, MSU 16H are described in U.S. Patent Nos. 5,576,298 and 5,837,685; Harrison, et al . , "Pseudomycins, a family of novel peptides from Pseudomonas syringae possessing broad-spectrum antifungal activity, " J . Gen . Microbiology, 137, 2857-2865 (1991); and Lamb et al .
  • a strain of P. syringae that is suitable for production of one or more pseudomycins can be isolated from environmental sources including plants (e.g., barley plants, citrus plants, and lilac plants) as well as, sources such as soil, water, air, and dust.
  • a preferred stain is isolated from plants.
  • Strains of P. syringae that are isolated from environmental sources can be referred to as wild type.
  • wild type refers to a dominant genotype which naturally occurs in the normal population of P. syringae (e.g., strains or isolates of P. syringae that are found in nature and not produced by laboratory manipulation) .
  • wild type refers to a dominant genotype which naturally occurs in the normal population of P. syringae (e.g., strains or isolates of P. syringae that are found in nature and not produced by laboratory manipulation) .
  • the characteristics of the pseudomycin- producing cultures employed employed (P.
  • syringae strains such as MSU 174, MSU 16H, MSU 206, 25-B1, 7H9-1) are subject to variation. Hence, progeny of these strains (e.g., recombinants, mutants and variants) may be obtained by methods known in the art .
  • P. syringae MSU 16H is publicly available from the American Type Culture Collection, Parklawn Drive, Rockville, MD, USA as Accession No. ATCC 67028.
  • P . syringae strains 25-B1, 7H9-1, and 67 Hi were deposited with the American Type Culture Collection on March 23, 2000 and were assigned the following Accession Nos.:
  • Mutant strains of P. syringae are also suitable for production of one or more pseudomycins.
  • mutant refers to a sudden heritable change in the phenotype of a strain, which can be spontaneous or induced by known mutagenic agents, such as radiation (e.g., ultraviolet radiation or x-rays), chemical mutagens (e.g., ethyl methanesulfonate (EMS) , diepoxyoctane, N-methyl-N- nitro-N' -nitrosoguanine (NTG) , and nitrous acid), site- specific mutagenesis, and transposon mediated mutagenesis.
  • radiation e.g., ultraviolet radiation or x-rays
  • chemical mutagens e.g., ethyl methanesulfonate (EMS) , diepoxyoctane, N-methyl-N- nitro-N' -nitrosoguanine (NTG) , and
  • Pseudomycin-producing mutants of P. syringae can be produced by treating the bacteria with an amount of a mutagenic agent effective to produce mutants that overproduce one or more pseudomycins, that produce one pseudomycin (e.g., pseudomycin B) in excess over other pseudomycins, or that produce one or more pseudomycins under advantageous growth conditions. While the type and amount of mutagenic agent to be used can vary, a preferred method is to serially dilute
  • NTG to levels ranging from 1 to 100 ⁇ g/ml.
  • Preferred mutants are those that overproduce pseudomycin B and grow in minimal defined media.
  • Environmental isolates, mutant strains, and other desirable strains of P. syringae can be subjected to selection for desirable traits of growth habit, growth medium nutrient source, carbon source, growth conditions, amino acid requirements, and the like.
  • a pseudomycin producing strain of P. syringae is selected for growth on minimal defined medium such as N21 medium and/or for production of one or more pseudomycins at levels greater
  • Preferred strains exhibit the characteristic of producing one or more pseudomycins when grown on a medium including three or fewer amino acids and optionally, either a lipid, a potato product or combination thereof .
  • Recombinant strains can be developed by transforming the P . syringae strains, using procedures known in the art. Through the use of recombinant DNA technology, the P. syringae strains can be transformed to express a variety of gene products in addition to the antibiotics these strains produce. For example, one can modify the strains to introduce multiple copies of the endogenous pseudomycin- biosynthesis genes to achieve greater pseudomycin yield.
  • the organism is cultured with agitation in an aqueous nutrient medium including an effective amount of three or fewer amino acids, preferably glutamic acid, glycine, histidine, or a combination thereof.
  • glycine is combined with one or more of a potato product and a lipid.
  • Culturing is conducted under conditions effective for growth of P. syringae and production of the desired pseudomycin or pseudomycins. Effective conditions include temperatures from about 22 2 C to about 27 2 C, and a duration of about 36 hours to about 96 hours.
  • Controlling the concentration of oxygen in the medium during culturing of P. syringae is advantageous for production of a pseudomycin.
  • oxygen levels are maintained at about 5 to 50% saturation, more preferably about 30% saturation. Sparging with air, pure oxygen, or gas mixtures including oxygen can regulate the concentration of oxygen in the medium.
  • Controlling the pH of the medium during culturing of P. syringae is also advantageous.
  • Pseudomycins are labile at basic pH, and significant degradation can occur if the pH of the culture medium is above about 6 for more than about 12 hours.
  • the pH of the culture medium is maintained between 6 and 4.
  • P. syringae can produce one or more pseudomycins when grown in batch culture.
  • fed-bath or semi-continuous feed of glucose and optionally, an acid or base (e.g., ammonium hydroxide) to control pH enhances production.
  • Pseudomycin production can be further enhanced by using continuous culture methods in which glucose and ammonium hydroxide are fed automatically.
  • Choice of P. syringae strain can affect the amount and distribution of pseudomycin or pseudomycins produced.
  • strains MSU 16H and 67 HI each produce predominantly pseudomycin A, but also produce pseudomycin B and C, typically in ratios of 4:2:1.
  • Strain 67 Hi typically produces levels of pseudomycins about three to five fold larger than are produced by strain MSU 16H.
  • strain 25-B1 produces more pseudomycin B and less pseudomycin C.
  • Strain 7H9-1 are distinctive in producing predominantly pseudomycin B and larger amount of pseudomycin B than other strains. For example, this strain can produce pseudomycin B in at least a ten fold excess over either pseudomycin A or C .
  • the prodrug can be formed from an N-acyl semi-synthetic compound.
  • Semi-synthetic pseudomycin compounds may be synthesized by exchanging the N-acyl group on the L-serine unit. Examples of various N-acyl derivatives are described in PCT Patent Application Serial No. , Belvo, et al . , filed evendate herewith entitled
  • the pendant amino groups at positions 2, 4 and 5 may be protected using any standard means known to those skilled in the art for amino protection.
  • the exact genus and species of 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).
  • Suitable amino-protecting groups include benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-methoxybenxyloxycarbonyl, p-methoxyphenylazobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl , t-butyloxycarbonyl , cyclopentyloxycarbonyl, and phthalimido.
  • Preferred amino protecting groups are t-butoxycarbonyl (t-Boc), allyloxycarbonyl (Alloc) , phthalimido, and benzyloxycarbonyl (CbZ or CBZ) .
  • Suitable protecting groups are described in T.W. Greene, "Protective Groups in Organic Synthesis,” John Wiley and Sons, New York, N.Y. , (2nd ed., 1991), at chapter 7.
  • the deacylation of a N-acyl group having a gamma or delta hydroxylated side chain may be accomplished by treating the amino- protected pseudomycin compound with acid in an aqueous solvent.
  • Suitable acids include acetic acid and trifluoroacetic acid. A preferred acid is trifluoroacetic acid. If trifluoroacetic acid is used, the reaction may be accomplished at or near room temperature.
  • Suitable aqueous solvent systems include acetonitrile, water, and mixtures thereof. Organic solvents accelerate the reaction; however, the addition of an organic solvent may lead to other by-products .
  • Pseudomycin compounds lacking a delta or gamma hydroxy group on the side chain e.g., Pseudomycin B and C
  • Pseudomycin B and C may be deacylated enzymatically .
  • Suitable deacylase enzymes include Polymyxin Acylase (164-16081 Fatty Acylase (crude) or 161-16091 Fatty Acylase (pure) available from Wako Pure Chemical Industries, Ltd.), or ECB deacylase.
  • the enzymatic deacylation may be accomplished using standard deacylation procedures well known to those skilled in the art.
  • general procedures for using polymyxin acylase may be found in Yasuda, N., et al, Agric . Biol . Chem . , 53, 3245 (1989) and Kimura, Y., et al . , Agri c . Biol . Chem . , 53, 497 (1989).
  • the deacylated product (also known as the pseudomycin nucleus) is reacylated using the corresponding acid of the desired acyl group in the presence of a carbonyl activating agent.
  • 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.
  • Such groups include, but are not limited to, alkoxy, aryloxy, nitrogen containing aromatic heterocycles, or amino groups (e.g., oxybenzotriazole, imidazolyl, nitrop enoxy, pentachlorophenoxy, N-oxysuccinimide, N,N'- dicyclohexylisoure-O-yl, and N-hydroxy-N-methoxyamino) ; acetates; formates; sulfonates (e.g., methanesulfonate, ethanesulfonate, benzenesulfonate, and p-tolylsulfonate) ; and halides (e.g., chloride, bromide, and iodide).
  • amino groups e.g., oxybenzotriazole, imidazolyl, nitrop enoxy, pentachlorophenoxy, N-oxysuccinimide, N,N'- dicycl
  • acids may be used in the acylation process. Suitable acids include aliphatic acids containing one or more pendant aryl, alkyl, amino (including primary, secondary and tertiary amines) , hydroxy, alkoxy, and amido groups; aliphatic acids containing nitrogen or oxygen within the aliphatic chain; aromatic acids substituted with alkyl, hydroxy, alkoxy and/or alkyl amino groups; and heteroaromatic acids substituted with alkyl, hydroxy, alkoxy and/or alkyl amino groups.
  • a solid phase synthesis may be used where a hydroxybenzotriazole-resin (HOBt-resin) serves as the coupling agent for the acylation reaction.
  • HOBt-resin hydroxybenzotriazole-resin
  • the amino protecting groups (at positions 2, 4 and 5) can be removed by hydrogenation in the presence of a hydrogenation catalyst (e.g., 10% Pd/C) .
  • a hydrogenation catalyst e.g. 10% Pd/C
  • the amino protecting group is allyloxycarbonyl
  • the protecting group can be removed using tributyltinhydride and triphenylphosphine palladium dichloride.
  • the prodrug is then produced by acylating at least one of the pendant amino groups attached to the lysine or 2,4- diaminobutyric acid peptide units of the N-acyl modified semi-synthetic pseudomycin compound to form the desired carbamate linkage.
  • modified prodrug pseudomycin compounds may be synthesized by amidation or esterification of the pendant carboxylic acid group of the aspartic acid and/or hydroxyaspartic acid units of the pseudomycin ring.
  • Examples of various acid-modified derivatives are described in PCT Patent Application Serial No. , Chen, et al . , filed evendate herewith entitled "Pseudomycin Amide & Ester Analogs" and incorporated herein by reference.
  • the acid- modified derivatives may be formed by condensing any of the previously described prodrugs with the appropriate alcohol or amine to produce the respective ester or amide.
  • Esterification under acidic conditions typically includes dissolving or suspending the pseudomycin compound in the appropriate alcohol in the presence of a protic acid (e.g., HCl, TFA, etc.).
  • a protic acid e.g., HCl, TFA, etc.
  • the pseudomycin compound is generally reacted with the appropriate alkyl halide in the presence of a weak base (e.g., sodium bicarbonate and potassium carbonate) .
  • a weak base e.g., sodium bicarbonate and potassium carbonate
  • amide groups may be accomplished using standard amidation procedures well-known to those skilled in the art.
  • the choice of coupling agents provides selective modification of the acid groups.
  • the use of benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate(PyBOP) as the coupling agent allows one to isolate pure mono-amides at residue 8 and (in some cases) pure bis amides simultaneously.
  • the use of o- benzotriazol-l-yl-N,N,N' ,N' -tetramethyluronium tetrafluoroborate (TBTU) as the coupling agent favors formation of monoamides at residue 3.
  • TBTU o- benzotriazol-l-yl-N,N,N' ,N' -tetramethyluronium tetrafluoroborate
  • the pseudomycin prodrug may be isolated and used per se or in the form of its pharmaceutically acceptable salt or solvate.
  • the prodrug is prepared by forming at least one acyloxyalkylcarbamate linkage as described earlier.
  • pharmaceutically acceptable salt refers to non-toxic acid addition salts derived from inorganic and organic acids.
  • Suitable salt derivatives include halides, thiocyanates, sulfates, bisulfates, sulfites, bisulfites, arylsulfonates, alkylsulfates, phosphonates, monohydrogen- phosphates, dihydrogenphosphates , metaphosphates, pyrophosphonates, alkanoates, cycloalkylalkanoates, arylalkonates, adipates, alginates, aspartates, benzoates, fumarates , glucoheptanoates, glycerophosphates, lactates, maleates, nicotinates, oxalates, palmitates, pectinates, picrates, pivalates, succinates, tartarates, citrates, camphorates, camphorsulfonates, digluconates, trifluoroacetates, and the like.
  • solvate refers to an aggregate that comprises one or more molecules of the solute (i.e., pseudomycin prodrug compound) with one or more molecules of a pharmaceutical solvent, such as water, ethanol, and the like.
  • a pharmaceutical solvent such as water, ethanol, and the like.
  • the solvent is water, then the aggregate is referred to as a hydrate.
  • Solvates are generally formed by dissolving the prodrug in the appropriate solvent with heat and slowing cooling to generate an amorphous or crystalline solvate form.
  • pseudomycin, semi-synthetic pseudomycin, pseudomycin prodrug and mixtures can be detected, determined, isolated, and/or purified by any variety of methods known to those skilled in the art.
  • the level of pseudomycin or pseudomycin prodrug activity in a broth or in an isolate or purified composition can be determined by antifungal action against a fungus such as
  • Candida and can be isolated and purified by high performance liquid chromatography .
  • the active ingredient i.e., pseudomycin prodrug
  • the active ingredient is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient, physician or veterinarian an elegant and easily handleable product.
  • Formulations may comprise from 0.1% to 99.9% by weight of active ingredient, more generally from about 10% to about 30% by weight.
  • the term "unit dose” or "unit dosage” refers to physically discrete units that contain a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect. When a unit dose is administered orally or parenterally, it is typically provided in the form of a tablet, capsule, pill, powder packet, topical composition, suppository, wafer, measured units in ampoules or in multidose containers, etc.
  • a unit dose may be administered in the form of a dry or liquid aerosol which may be inhaled or sprayed.
  • the dosage to be administered may vary depending upon the physical characteristics of the animal, the severity of the animal's symptoms, the means used to administer the drug and the animal species. The specific dose for a given animal is usually set by the judgment of the attending physician or veterinarian.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the active ingredient is being applied.
  • the formulations may also include wetting agents, lubricating agents, surfactants, buffers, tonicity agents, bulking agents, stabilizers, emulsifiers, suspending agents, preservatives, sweeteners, perfuming agents, flavoring agents and combinations thereof.
  • a pharmaceutical composition may be administered using a variety of methods. Suitable methods include topical (e.g., ointments or sprays), oral, injection and inhalation. The particular treatment method used will depend upon the type of infection being addressed.
  • the formulations are typically diluted or reconstituted (if freeze-dried) and further diluted if necessary, prior to administration.
  • An example of reconstitution instructions for the freeze-dried product are to add ten ml of water for injection (WFI)to the vial and gently agitate to dissolve. Typical reconstitution times are less than one minute.
  • the resulting solution is then further diluted in an infusion solution such as dextrose 5% in water (D5W) , prior to administration.
  • Pseudomycin compounds have been shown to exhibit antifungal activity such as growth inhibition of various infectious fungi including Candida spp. (i.e., C. albicans, C. parapsilosis , C. krusei , C. glabrata, C. tropicalis, or
  • Torulopus spp. i.e., T. glabrata
  • Aspergillus spp. i.e., A . fumigatus
  • H. capsulatum i.e., H. capsulatum
  • Cryptococcus spp. i.e., C. neoformans
  • Blastomyces spp. i.e., B. dermati tidis
  • Fusarium spp. i.e., Trichophyton spp., Pseudallescheria boydii ,
  • a method for inhibiting fungal activity comprising contacting the pseudomycin prodrug of the present invention with a fungus.
  • a preferred method includes inhibiting Candida albicans or Aspergillus fu igatus activity.
  • the term "contacting" includes a union or junction, or apparent touching or mutual tangency of a compound of the invention with a fungus. The term does not imply any further limitations to the process, such as by mechanism of inhibition.
  • the methods are defined to encompass the inhibition of parasitic and fungal activity by the action of the compounds and their inherent antifungal properties.
  • a method for treating a fungal infection which comprises administering an effective amount of a pharmaceutical formulation of the present invention to a host in need of such treatment is also provided.
  • a preferred method includes treating a Candida albicans, Cryptococcus neoformans, or Aspergillus fumigatus infection.
  • the term "effective amount" refers to an amount of active compound 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, the tolerance of the host to the antifungal agent and the species of the host.
  • the particular dose regimen likewise may vary according to these factors.
  • the medicament may be given in a single daily dose or in multiple doses during the day. The regimen may 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 between about 0.01 mg/kg to 100 mg/kg of body weight of an active compound.
  • Preferred daily doses are generally between about 0.1 mg/kg to 60 mg/kg and more preferably between about 2.5 mg/kg to 40 mg/kg.
  • the host is generally an animal including humans, companion animals (e.g., dogs, cats and horses), food-source animals (e.g., cows, pigs, sheep and poultry), zoo animals, marine animals, birds and other similar animal species.
  • CBZ benzyloxycarbonyl, C 6 H 5 CH 2 -0-C (0) -
  • PyBOP benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate
  • TBTU o-Benzotriazol-l-yl-N,N,N' ,N' -tetramethyluroniu tetrafluoroborate
  • DIEA N,N-diisopropylethylamine
  • Antifungal activity was determined in vi tro by obtaining the minimum inhibitory concentration (MIC) of the compound using a standard agar dilution test or a discdiffusion test. A typical fungus employed in testing antifungal activity is Candida albicans . Antifungal activity is considered significant when the test sample (50 ⁇ l) causes 10-12 mm diameter zones of inhibition on C. albicans x657 seeded agar plates.
  • Tail Vein Toxici ty is considered significant when the test sample (50 ⁇ l) causes 10-12 mm diameter zones of inhibition on C. albicans x657 seeded agar plates.
  • mice were treated intravenously (IV) through the lateral tail vein with 0.1 ml of testing compound (20 mg/kg) at 0, 24, 48 and 72 hours. Two mice were included in each group. Compounds were formulated in 5.0% dextrose and sterile water for injection. The mice were monitored for 7 days following the first treatment and observed closely for signs of irritation including erythema, swelling, discoloration, necrosis, tail loss and any other signs of adverse effects indicating toxicity.
  • mice used in the study were outbred, male ICR mice having an average weight between 18-20 g (available from Harlan Sprangue Dawley, Indianapolis, IN). Prepara tions
  • R 1' , R 1" and R 1'" H
  • R 2 -NH(cyclopropyl)
  • R 3 -OH
  • the 3-amido compound (279.1 mg, 0.169 mmol) was hydrogenated under hydrogen balloon catalyzed by 10% Pd/C in 1% HOAc/MeOH for 45 minutes. The reaction was filtered and concentrated in vacuo . The residue was picked up in a 1:1 mixture of water :ACN and then lyophilized to give 208.3 mg (98.6%) of a colorless powder (2b-l) . The structure was verified by H 1 -NMR.
  • Carbinol 4c-l (6.22 g, 22.0 mmol) was dissolved in an aqueous THF solution (5.5 mL water and 55 mL THF) . To this solution was added NMO (4.42 g, 33.0 mmol), followed by OSO 4 (280 mg dissolved in THF, 1.10 mmol) . The reaction stirred at rt overnight. At this time, sodium bisulfide (4 g) was added. The reaction was stirred for 2 hr, and then diluted with EtOAc (300 mL) . The whole mixture was washed with water (2 x 40 mL) and brine. The resulting organic layer was dried and cone . in vacuo to give the corresponding triol intermediate.
  • n is equal to 10, 12 and 14 have also been made using the same procedure described above.
  • Sample 4-1 was not tested. Samples 4-3, 4-4 and 4-5 all demonstrated negative tail vein toxicity. Samples 4-2, 4-3, 4-4 and 4-5 all demonstrated in vivo efficacy against murine systemic Candidiasis.
  • Examples 8 and 9 illustrate the synthesis of prodrugs from semi-synthetic pseudomycin compounds where the pendant N-acyl group of the L-serine unit of the pseudomycin structure has been modified.
  • the trisubstituted compound demonstrated negative tail vein toxicity.
  • Example 10 illustrates further modification of the above described prodrugs where the carboxylic acid group of the aspartic acid unit of the pseudomycin ring is modified to form a 3-monoamido derivative.
  • R 1' , R 1" , R 1"' -C(0)OCH 2 OC(0)C(CH 3 ) 3
  • R 2 -NHCH 2 CH 2 N (CH 3 ) 2
  • R 3 -OH 10-1
  • R 1 ' , R 1 " , R 1 ' “ -C (0) OCH 2 OC (0 ) C (CH 3 ) 3
  • R 2 -NH ( cyclopropyl )
  • Compound 10-2 is synthesized using the same procedures as above except 0.052 mmol of cyclopropylamine is used in place of the l-dimethylamino-2-aminoethane .
  • R 1' , R 1" , R 1'" -C(0)OCH 2 OC(0)C(CH 3 ) 3
  • R 2 -NHCH 2 (C0 2 CH 3 )
  • R 3 -OH
  • Compound 10-3 is synthesized using the same procedures as above except glycine methyl ester is used in place of the l-dimethylamino-2-aminoethane .
  • R 1' , R 1" , R 1"' -C(0)OCH 2 OC(0)CH(CH 3 ) 2
  • R 2 -NHCH 2 CH 2 N(CH 3 ) 2
  • R 3 -OH
  • R 1' , R 1" , R 1'" -C(0)OCH 2 OC(0)CH(CH 3 ) 2
  • R 2 -NH(cyclopropyl)
  • R 3 -OH
  • Compound 10-5 is synthesized using the same procedures as above except 0.052 mmol of prodrug 7-1 is used in place of the prodrug 3-5 and 0.052 mmol of cyclopropylamine is used in place of the l-dimethylamino-2-aminoethane .
  • Example 11 illustrates the formation of the prodrug of pseudomycin compounds where the carboxylic acid group of the aspartic acid unit of the pseudomycin ring has been modified to form a 3-ami o derivative. Synthesis of 3-monoamido derivative 11 -1
  • Example 12 illustrates the synthesis of a prodrug where the carboxylic acid group of both the aspartic acid and hydroxyaspartic acid units have been modified to form a bis- ester derivative.

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Abstract

L'invention concerne un promédicament de pseudomycine représenté par la structure (A) dans laquelle R1 désigne une liaison d'acyloxyalkylcarbamate. Le promédicament fait preuve d'une activité antifongique avec effets secondaires réduits.
PCT/US2000/015016 1999-07-15 2000-06-08 Promedicaments de pseudomycine WO2001005813A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU53105/00A AU5310500A (en) 1999-07-15 2000-06-08 Pseudomycin prodrugs
JP2001511470A JP2003505396A (ja) 1999-07-15 2000-06-08 プソイドマイシンプロドラッグ
BR0013153-9A BR0013153A (pt) 1999-07-15 2000-06-08 Pró-drogas de pseudomicina
EP00938005A EP1198470A1 (fr) 1999-07-15 2000-06-08 Promedicaments de pseudomycine
EA200200161A EA200200161A1 (ru) 1999-07-15 2000-06-08 Пролекарства псевдомицина
CA002379058A CA2379058A1 (fr) 1999-07-15 2000-06-08 Promedicaments de pseudomycine
MXPA02000315A MXPA02000315A (es) 1999-07-15 2000-06-08 Profarmacos de pseudomicina.
NO20020192A NO20020192L (no) 1999-07-15 2002-01-14 Pseudomycin prodrug

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US14384099P 1999-07-15 1999-07-15
US60/143,840 1999-07-15

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Cited By (8)

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US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
WO2005066122A2 (fr) * 2003-12-30 2005-07-21 Xenoport, Inc. Synthese de promedicaments a base de carbamate d'acyloxyalkyle et leurs intermediaires
US7351740B2 (en) 2005-06-20 2008-04-01 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
US7531572B2 (en) 2006-07-28 2009-05-12 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of α-amino acids, methods of synthesis and use
WO2010017498A1 (fr) * 2008-08-07 2010-02-11 Xenoport, Inc. Procédés de synthèse de carbonates de n-hydroxysuccinimidyle
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US9944592B2 (en) 2003-08-20 2018-04-17 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use

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CN1902175B (zh) * 2003-12-30 2012-08-22 什诺波特有限公司 酰氧基烃基氨基甲酸酯前药及其中间体的合成

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US5576298A (en) * 1992-11-30 1996-11-19 Research And Development Institute, Inc. At Montana State University Peptides from pseudomonas syringae possessing broad-spectrum antibiotic activity
US5837685A (en) * 1992-11-30 1998-11-17 Research And Development Institute Inc. At Montana State University Peptides from Pseudomonas syringae possessing broad-spectrum antibiotic activity

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CHEN E.A.: "Syntheses and biological evaluation of novel pseudomycin side-chain analogues. Part 2", BIOORG.MED.CHEM.LETT., vol. 10, no. 18, 2000, pages 2107 - 2110, XP004208322 *
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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US10385014B2 (en) * 2003-08-20 2019-08-20 Arbor Pharmaceuticals, Llc Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
US9944592B2 (en) 2003-08-20 2018-04-17 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs, methods of synthesis and use
US7511158B2 (en) 2003-12-30 2009-03-31 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
EP2371815A1 (fr) 2003-12-30 2011-10-05 XenoPort, Inc. Synthèses de promédicaments à base de carbamate d'acyloxyalkyle et intermédiaires associés
WO2005066122A2 (fr) * 2003-12-30 2005-07-21 Xenoport, Inc. Synthese de promedicaments a base de carbamate d'acyloxyalkyle et leurs intermediaires
WO2005066122A3 (fr) * 2003-12-30 2005-10-13 Xenoport Inc Synthese de promedicaments a base de carbamate d'acyloxyalkyle et leurs intermediaires
US9353057B2 (en) 2003-12-30 2016-05-31 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
US7227028B2 (en) 2003-12-30 2007-06-05 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
US8378137B2 (en) 2003-12-30 2013-02-19 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
US8003809B2 (en) 2003-12-30 2011-08-23 Xenoport, Inc. Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7351740B2 (en) 2005-06-20 2008-04-01 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
US8372881B2 (en) 2005-06-20 2013-02-12 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
US7777070B2 (en) 2005-06-20 2010-08-17 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
US7592369B2 (en) 2005-06-20 2009-09-22 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use
US7531572B2 (en) 2006-07-28 2009-05-12 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of α-amino acids, methods of synthesis and use
US7799829B2 (en) 2006-07-28 2010-09-21 Xenoport, Inc. Acyloxyalkyl carbamate prodrugs of α-amino acids, methods of synthesis and use
US7989641B2 (en) 2008-08-07 2011-08-02 Xenoport, Inc. Methods of synthesizing N-hydroxysuccinimidyl carbonates
WO2010017498A1 (fr) * 2008-08-07 2010-02-11 Xenoport, Inc. Procédés de synthèse de carbonates de n-hydroxysuccinimidyle

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AU5310500A (en) 2001-02-05
NO20020192D0 (no) 2002-01-14
MXPA02000315A (es) 2002-06-21
HUP0202223A3 (en) 2002-11-28
EA200200161A1 (ru) 2002-06-27
JP2003505396A (ja) 2003-02-12
NO20020192L (no) 2002-03-14
BR0013153A (pt) 2002-04-02

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