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WO2008140973A1 - Glycopeptides semi-synthétiques à activité antibactérienne - Google Patents

Glycopeptides semi-synthétiques à activité antibactérienne Download PDF

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WO2008140973A1
WO2008140973A1 PCT/US2008/062483 US2008062483W WO2008140973A1 WO 2008140973 A1 WO2008140973 A1 WO 2008140973A1 US 2008062483 W US2008062483 W US 2008062483W WO 2008140973 A1 WO2008140973 A1 WO 2008140973A1
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compound
hydrogen
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alkyl
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Daniel Chu
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Lead Therapeutics Inc
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Lead Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Naturally occurring and semi-synthetic glycopeptide antibiotics used to combat bacteria infections include compounds such as vancomycin, desmethylvancomycin, eremomycm, teicoplanin (complex of five compounds), dalbavancin, o ⁇ tavancin, telavancm, and A82846B (LY264826) having structures A, B, C, D, E, F, G and H
  • Compound B, Compound H or Compound C scaffolds to provide novel semi-synthetic glycopeptides that have antibacterial activity, as well as their pharmaceutical acceptable salts, esters, solvates, alkylated quaternary ammonium salts, stereoisomers, tautomers or prodrugs thereof, and which can be used as antibacterial agents for treatment of bacterial infections with superior microbiology and pharmacokinetic properties than currently available glycopeptide antibacterial agents.
  • R A is selected from the group consisting of a) hydrogen, b) methyl, c) C 2 -C 12 -alkyl;
  • R 1 and R 2 are each independently selected from the group consisting of a) hydrogen, b) d-C.-alkyl, c) Ci-C 12 -alkyl substituted with one or more substituents selected from the group consisting of
  • R 1 and R 2 taken together with the atom to which they are attached form a 3-10 membered heterocycle ring which optionally contains one to three heteroatom or hetero functionalities selected from the group consisting of -O- , -NH, -N(C r C 6 -alkyl)-, -N(aryl)-, -N(aryl- C,-C 6 -alkyl-
  • n 1 or 2 and the 3-10 membered heterocycle ring optionally substituted with one or more substituents independently selected from the group consisting of (a) halogen,
  • R 7 is selected from the group consisting of a) hydrogen, b) Crdralkyl, c) C ! -C 12 -alkyl substituted with one or more substituents selected from the group consisting of (a) halogen,
  • X is selected from the group consisting of (1) hydrogen,
  • R is selected from the group consisting of
  • R 5 and Re are taken together with the atom to which they are attached from a 3- 10 membered heterocycloalkyl ring which is optionally substituted with one or more substituents independently selected from the group consisting of
  • R 3 is selected from the group consisting of
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl or
  • Rg and R 9 together with the atom to which they are attached from a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of
  • R 4 is selected from the group consisting of
  • aminoloweralkyl wherein the amino portion of the ammoloweralkyl group is further substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof
  • the compound has the structure of Formula I
  • the compound has the structure of Formula II or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, wherein R, etc. have the meanings defined in claim 1.
  • the compound has the structure of Formula II or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, wherein R, etc have the meanings defined in claim 1.
  • the compound has the structure of Formula III
  • the compound has the structure of Formula IV
  • R A is methyl and R 4 is hydrogen
  • R A is hydrogen and R 4 is hydrogen
  • X is hydrogen and R 4 is hydrogen.
  • X is chlorine and R 4 is hydrogen.
  • R A is methyl and R 4 is CH 2 NHCH 2 PO 3 H 2 .
  • R A is hydrogen and R 4 is CH 2 NHCH 2 PO 3 H 2 .
  • R 3 is selected from the group consisting of (1) OH,
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl or
  • Rg and Rg together with the atom to which they are attached from a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of
  • R 3 is OH In an alternative embodiment, R 3 is 2-adamantanammo
  • Rj and R 2 are each independently selected from the group consisting of a) hydrogen, b) C 1 -C ⁇ 12 alkyl, c) C r C 12 -alkyl substituted with one or more substituents selected from the group consisting of
  • Ri and R 2 taken together with the atom to which they are attached from a 3-10 membered heterocycle ⁇ ng which optionally contains one to three heteroatom or hetero functionalities selected from the group consisting of-O-, -NH, -N(C r C 3 -alkyl)-, -N(aryl)-, -N(aryl- C r C 6 -alkyl-
  • R 1 and R 2 are hydrogen
  • R 1 and R 2 are hydrogen
  • R 1 and R 2 are hydrogen
  • R 1 and R 2 are compounds having a structure selected from the group consisting of
  • R A IS hydrogen or methyl
  • X is chlorine or hydrogen
  • R 4 is hydrogen or CH 2 NHCH 2 PO 3 H 2
  • L is a leaving group such as OMs, OTs, OTf, halogen and the like
  • R A is hydrogen or methyl
  • X is chlorine or hydrogen
  • R 4 is hydrogen or CH 2 NHCH 2 POsH 2 , or aminoloweralkyl as defined herein
  • R 3 is previous defined with the proviso R 3 is not OH
  • L is a leaving group such as OMs, OTs, halogen and the like
  • R 1 is hydrogen and R 2 is COCHRNHRio wherein R ⁇ is substituted arylalkyl and R is previous defined
  • Des-4-epivancosaminyl A82846B mesylate (15), Des-4- epivancosammyl eremomycin mesylate (16).
  • Desvancosaminyl vancomycin azide (17), Desvancosaminyl desmethylvancomycm azide (18), Des-4-epivancosaminyl A82846B azide (19), Des-4-epivancosaminyl eremomycin azide (20), Desvancosaminyl vancomycin amine (21), Desvancosaminyl desmethylvancomycm amine (22), Des-4- epivancosaminyl A82846B amine (23), Des-4-eptvancosaminyl eremomycin amine (24), Nitro-desvancosaminyl vancomycin (25).
  • Nitro-desvancosaminyl demethylvancomycm (26). Nitro-des-4-epivancosamrnyl A82846B (27), Nitro-des-4-epivancosaminyl eremomycin (28), Amino-desvancosaminyl vancomycin (29), Ammo-desvancosaminyl demethylvancomycm (30), Amino-des-4-epivancosammyl A82846B (31), Amino-des-4-epivancosaminyl eremomycin (32), Adamantyl-2-ammo desvancosaminyl vancomycin amide (33).
  • Adamantyl-2-amino- desvancosaminyl desmethylvancomycm amide (34).
  • Adamantyl-l-ammo-des-4-e ⁇ ivancosaminyl A82846B amide (35),
  • Adamantyl-2-amino-Des-4-epivancosammyl eremomycin amide (36), Desvancosaminyl vancomycin nitrile (37), Desvancosaminyl desmethylvancomycm mtrile (3_8), Des-4-epivancosaminyl A82846B nitrile (39), Des-4- epivancosaminyl eremomycin (40), Adamantyl-2-ammo desvancosaminyl vancomycin amide (41).
  • a mammal in need of such treatment comprising administering to the mammal an antibacte ⁇ ally effective amount of any of the aforementioned compounds together with a pharmaceutically acceptable carrier
  • a pharmaceutically acceptable carrier i e , a compound of any of Formula I, Formula II, Formula III or Formula IV
  • described herein is the use of a compound desc ⁇ bed herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) m the manufacture of a medicament for the treatment of a bacterial-related disease or condition
  • a compound described herein i e , a compound of any of Formula I, Formula H, Formula III or Formula IV
  • Non-limiting examples include antibacterial soaps and cleaning products
  • a compound described herein i e , a compound of any of Formula I, Formula II, Formula III or Formula IV
  • a compound desc ⁇ bed herein i e , a compound of any of Formula I, Formula II, Formula III or Formula IV
  • another antibacterial agent including a different compound desc ⁇ bed herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) or any other antibacterial agent (e g , Amdinocillm, Amikacin, Amoxicillin, Ampicillm, Atovaquone, Azithromycin, Aztreonam, Bacampicillin, Bacitracin, Capreomycin, Carbenicillm mdanyl sodium, Cefaclor, Cefadroxil, Cefamandole, Cefazolm,
  • articles of manufacture comprising packaging material, a compound of any of Formula I, Formula II, Formula III or Formula IV, which is effective for treatment, prevention or amelioration of one or more symptoms of a bacterial-mediated disease or condition, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable acyl glucuroide metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for treatment, prevention or amelioration of one or more symptoms of a bacterial-mediated disease or condition, are provided [0028]
  • methods of making a compound of Formulas I-IV comprising modifying a compound from the group consisting of Formulas i, ii, iii and iv,
  • R A is hydrogen or methyl
  • X is chlorine or hydrogen
  • R 4 is hydrogen or CH 2 NHCH 2 PO 3 H 2
  • ammoloweralkyl as defined herein, by a technique selected from the group consisting of, (a) alkylation of the amino substituent on the amino-substituted sugar moiety of the 4 th ammo acid of the compound with an alkyl halide having structure Rj-J where J is a halogen
  • R, R 1 , R 2 , R 3 , R 4 , R A , and X are as defined herein
  • novel semi-synthetic glycopeptides that have antibacterial activity
  • the semi-synthetic glycopeptides described herein are based on hydrolysis of the disaccha ⁇ de moiety of the amino acid-4 of the parent glycopeptide to monosaccharide, conversion of the monosaccharide to the ammo-sugar, acylation of the amino substituent on the ammo-substituted sugar moiety on these scaffolds with certain acyl groups, and conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides
  • R A is selected from the group consisting of a) hydrogen, b) methyl, c) C 2 -C 12 -alkyl, Ri and R 2 are each independently selected from the group consisting of a) hydrogen, b) C r C 12 -alkyl, c) C]-C 12 -alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy,
  • R 7 is selected from the group consisting of a) hydrogen, b) C]-Ci2 -alkyl, c) C]-Ci2 -alkyl substituted with one or more substituents selected from the group consisting of
  • X is selected from the group consisting of
  • R is selected from the group consisting of
  • Ci-Ci2-alkyl (5) Ci-Ci 2 -alkyl substituted with one or more substituents selected from the group consisting of
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl or
  • R 8 and R 9 together with the atom to which they are attached from a 3-10 membered heterocycloalkyl ring, which optionally is substituted with one or more substituents independently selected from the group consisting of
  • R 4 is selected from the group consisting of
  • aminoloweralkyl wherein the amino portion of the aminoloweralkyl group is further substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy, or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof [0034] It will be observed above that in the disclosure that numerous asymmetric centers may exist in the compounds provided herein which will be found in the R or S configurations Excepted where otherwise noted, the compounds provided herein include the various stereoisomers and mixtures thereof
  • compositions which comprise a therapeutically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier
  • bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound provided herein, in such amounts and for such time as is necessary to achieve the desired result
  • R 1 is hydrogen and R 2 is selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl, and said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one ore more optionally substituted aryl, heteroaryl, or condensed rings,
  • R 2 is hydrogen or methyl substituted with an unsubstituted or substituted biphenyl, for example biphenyl or chloro-biphenyl
  • R 7 is selected from the group consisting of a) hydrogen, b) C r C 12 -alkyl, c) Q-C ⁇ -alkyl substituted with one or more substituents selected from the group consisting of
  • R 5 and R 6 are taken together with the atom to which they are attached from a 3- 10 membered heterocycloalkyl ring which optionally is substituted with one or more substituents independently selected from the group consisting of
  • R 3 and R 9 are independently selected from the group consisting of hydrogen, loweralkyl or substituted loweralkyl, cycloalkyl, substituted cycloalkyl or
  • R 8 and R 9 together with the atom to which they are attached from a 3-10 membered heterocycloalkyl rmg, which optionally is substituted with one or more substituents independently selected from the group consisting of
  • intermediate compounds of Formulas I, EI, HI and IV for the synthesis of antibacterial agents wherern R A is hydrogen or methyl, X is chlorme or hydrogen, R 4 is hydrogen, CH 2 NHCH 2 PO 3 H 2 , or aminoloweralkyl, R 3 is OH and Ri and R 2 are hydrogen
  • salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobrormc acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid
  • Further salts include those in which the counte ⁇ on is an anion, such as adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate
  • N-acyl derivatives of compounds of Formulas I, II, III, and IV are pharmaceutically acceptable N-acyl derivatives of compounds of Formulas I, II, III, and IV.
  • N-acyl groups include N-acetyl and N-ethoxycarbonyl groups. Definitions
  • alkyl refers to saturated, straight- or branched-cham hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom
  • alkenyl refers to unsaturated, straight- or branched-cham hydrocarbon radicals derived from a hydrocarbon moiety containing between two and twenty carbon atoms by removal of a single hydrogen atom
  • cycloalkyl refers to a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound containing between three and twenty carbon atoms by removal of a single hydrogen atom.
  • substituted cycloalkyl refers to cycloalkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylammo, dialkylarmno, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups
  • cycloalkenyl refers to a monovalent group derived from a monocyclic or bicyclic unsaturated carbocyclic ring compound containing between three and twenty carbon atoms by removal of a single hydrogen atom.
  • C r C 3 -alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom. Examples of C !
  • C -C 3 -alkyl radicals include methyl, ethyl, propyl and isopropyl
  • C r C 6 -alkyl radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl
  • radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl , n-hexyl.
  • loweralkyl refers to Ci-Ci 2 -alkyl as defined above
  • substituted loweralkyl refers to C]-Ci 2 -alkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylammo, dialkylarmno, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups
  • Cj-Ci 2 -cycloalkyl denoted a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic rmg compound by removeal of a single hydrogen atom Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1 ]heptyl, and bicyclo[2 2.2]octyl
  • C r C 3 -alkoxy refers to the C r C 3 -alkyl group and C 1 -
  • C ⁇ -alkyl group as previously defined, atttached to the parent molecular moiety through an oxygen atom
  • CpC ⁇ -alkoxy radicals include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • loweralkylamino refers to C r C 12 -alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom
  • loweralkylamrno include, but are not limited to methylamino, dimethylamino, ethylaimno, diethylamino, propylamino and decylamino
  • oxo denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl group as defined above are replaced with a single oxygen atom (i e a carbonyl group)
  • aryl as used herein refers to a mono- or bicychc carbocylic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, mdenyl and the like and can
  • substituted aryl refers to a mono- or bicychc carbocylic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, mdenyl and the like substituted (including bicychc aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, C r C 12 -alkoxy, thioalkoxy, aryloxy, amino, alkylamino, dialkylamino, acylarmno, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl,aryl, heteroaryl, heterocyclaryl and carboxamide
  • substituted aryl groups include tetrafluorophenyl and pentafluor
  • substituted arylalkyl refers to an substituted aryl group as defined above attached to the parent molecular moiety through an alkyl group wherein the alkyl group is of one to twelve carbon atoms
  • alkylaryl refers to an alkyl group as defined above attached to the parent molecular moiety through an aryl group
  • halo and "halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodme
  • alkylamino refers to a group having the structure -NHR' wherein R' is alkyl, as previously defined Examples of alkylamino include methylamino, ethylamino, lso-propylamino, and the like
  • dialkylamino refers to a group having the structure -NR'R" wherein R' and R" are independently selected from alkyl, as previously defined Additionally, R' and R" taken together optionally is - (CH 2 ) k - where k is an integer of from 2 to 6
  • dialkylamino include dimethylamino, diethylamino, methylpropylammo, pipe ⁇ dmo, and the like
  • haloalkyl denotes an alkyl group, as defined above, having one, two or three halogen atoms attached thereto and is exemplified by such group as chloromethyl, bromoethy
  • R" are independently selected from hydrogen, alkyl, substituted loweralkyl, or R' and R" taken together optionally is — (CH 2 ) k - where k is an integer of from 2 to 6
  • heteroaryl refers to a cyclic or bicyclic aromatic radical having from five to ten ring stoms in each rmg of which at least one atom of the cyclic or bicyclic ring is selected from optionally substituted S, O, and N, zero, one or two ring atoms are additional heteroatoms independently selected from optionally substituted S, O, and N, and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the rmg atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, lmidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, qurnolinyl, isoqumolinyl, nap
  • heterocycloalkyl refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered rmg system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which may include aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring
  • heterocycloalkyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms optionally is oxidized and the nitrogen heteroatom optionally is quaternized
  • Representative heterocycloalkyl rings include, but not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, lrmdazolinyl, lmidazolidinyl, pipendmyl, prperazrnyl, oxazolidinyl, lsoxazolidmyl, morpholinyl,
  • heteroarylalkyl refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group wherein the alkylene group is of one to four carbon atoms
  • Protecting group refers to an easily removable group which is known in the art to protect a functional group, for example, a hydroxyl, ketone or amine against undesirable reaction during synthetic procedures and to be selectively removable Examples of such protecting groups are known, cf , for example, T H Greene and P G M Wuts, Protective Groups in Organic Synthesis, 2 nd edition, John Wiley & Sons, New York (1991)
  • hydroxy-protecting groups include, but not limited to, mefhylfhiomethyl, tert-dimethylsilyl, tert- butyldiphenylsilyl, ethers such as methoxymethyl, and esters including acetyl, benzoyl, and the
  • ammo acid refers to ammo acids having D or L stereochemistry, and also refers to synthetic, non-natural ammo acids having side chains other than those found in the 20 common amino acids
  • Non- natural amino acids are commercially available or are prepared according to US 5,488, 131 and references therein
  • Amino acids are further substituted to contain modifications to their amino, carboxy, or side-cham groups These modifications include the numerous protecting group commonly used in peptide synthesis (T H Greene and P G M Wuts, Protective Groups m Organic Synthesis.
  • substituted heteroaryl refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, Ci-C ⁇ -alkyl, C r Ci 2 -alkoxy, C r Ci 2 -alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, mtro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide
  • any one substituent is optionally an aryl, heteroaryl, or hetercycloalkyl group
  • substituted heterocycloalkyl refers to a heterocycloalkyl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C r C 12 -alkyl, CpC ⁇ -alkoxy, Q-C ⁇ -alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, mtro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide
  • any one substituent is optionally an aryl, heteroaryl, or hetercycloalkyl group
  • stereoisomer refers to either of two forms of a compound having the same molecular formula and having their constituent atoms attached in the same order, but having different arrangement if their atoms in space about an asymmetric center.
  • tautomer refers to either of the two forms of a chemical compound that exhibits tautomensm, which is the ability of certain chemical compounds to exist as a mixture of two interconvertible isomers in equilibrium via proton transfer
  • the keto and enol forms of carbonyl compounds are examples of tautomers They are interconvertible in the presence of traces of acids and bases via a resonance stabilized anion, the enolate ion
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio For example, S.
  • salts can be prepared in situ during the final isolation and purification of the compounds described herem compound described herem (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV), or separately by reacting the free base function with a suitable organic acid
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succmic acid or malonic acid or by using other methods used in the art such as ion exchange
  • Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counte ⁇ ons such as hahde, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate
  • pharmaceutically acceptable ester refers to esters which hydrolyze in vivo and include those that break down in the human body to leave the parent compound or a salt thereof
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms
  • Representative examples of particular esters include, but are not limited to, formates
  • solvate refers to a compound formed by salvation, the combination of solvent molecules with molecules or ions of solute composed of a compound described herein
  • pharmaceutically acceptable solvate refers to those solvates which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lover animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio
  • alkylated quaternary ammonium salt refers to a compound formed by alkylation of the nitrogen atom of the primary, secondary or tertiary amine of the molecule with alkyl hahde to form alkyl quaternary ammonium salt
  • prodrugs refers to those prodrugs of the compounds described herein compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitte ⁇ omc forms, where possible, of the compounds described herein
  • prodrug refers to compounds that are transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood A thorough discussion is provided m T Higuchi and V Stella, Pro-drugs as Novel Delivery Systems, VoI 14 of the A C S Symposium Series, and in Edward B Roche, ed , Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference Syn
  • Formula III or Formula IV can be broadly summarized as follows
  • the compounds described herein are optionally made by chemical modifications of the Compound A, Compound B, Compound H and Compound C scaffolds
  • the semi-synthetic glycopeptides described herein are made by subjecting the parent glycopeptide in acidic medium to hydrolyze the disaccha ⁇ de moiety of the amino acid-4 of the parent glycopeptide to give the monosaccharide, conversion of the monosaccharide to the amino-sugar derivative, acylation of the amino substituent on the ammo-substituted sugar moiety on these scaffolds with certain acyl groups, and conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides
  • the compounds described herein are optionally made by coupling the ammo-sugar moiety of functionalized or unfunctionahzed glycopeptides from the above scaffolds with the appropriate acyl and/or amino groups under amide formation conditions and conversion of the acid moiety on the macrocyclic
  • the symi-synthetic glycopeptides of the compounds described herein are optionally made by modifying Compound A, Compound B, Compound H and Compound C scaffolds
  • the glycopeptide starting material is optionally unsubstituted or substituted at the 7 th amino acid at the 4' position of the phenyl ring with CH 2 NHCH 2 PO 3 H 2 , or aminoloweralkyl as defined herein
  • substitutions at R 4 are optionally introduced via Mannich reaction wherein the glycopeptide is treated with an amine and formaldehyde under basic conditions (for example, as described in The Journal of Antibiotics, VoI 50, No 6, p 509-513)
  • R A is hydrogen or methyl
  • X is chlorine or hydrogen
  • R 4 is hydrogen or CH 2 NHCH 2 PO 3 H 2 , or amrnoloweralkyl as defined herein, by a technique selected from the group consisting of,
  • R, Ri, R 2 , R 3 , R 4 , R A , and X are as defined herein.
  • the semi-synthetic glycopeptides described herein are made by firstly conversion of the acid moiety on the macrocyclic ring of the parent glycopeptide (Compound A, Compound B, Compound H or Compound C) to certain substituted amides.
  • the symi-synthetic glycopeptides described herein are optionally made by modifying
  • Conversion the amino acid -4 monosaccha ⁇ des derivatives [9] and [10] to the synthetic intermediate ammo acid-4 ammo-sugar derivatives can be achieved as follow 1) temporary protection of the amino group(s) of the molecules with t-butoxycarbonyl group, 2) activating the primary alcohol of the monosaccharide to a leaving group, such as mesylate, tosylate, triflate and the like, to give glycopeptides [11] and [12], respectively, wherein R A IS hydrogen or methyl, X is chlorine or hydrogen, R 4 is hydrogen or CH 2 NHCH 2 POsH 2 , or armnoloweralkyl as defined herein, R 3 is previous defined with the proviso R 3 is not OH, and L is a leaving group such as OMs, OTs, halogen and the like, 4) displacement of the leaving group with sodium azide to form the azido derivative and 5) reduction of the azide group to give the corresponding synthetic intermediate amino-sugar derivative
  • Formulas II and IV can be achieved as follow. 1) displacement of the leaving group in compounds of Formulas [11] and [12] with nitromethane in basic condition to form the mtro-derivatives and 2) reduction of the nitro group to give the corresponding synthetic intermediate ammo acid-4 amino-sugar derivatives of Formulas II and IV for the synthesis of antibacterial semi-synthetic glycopeptides, wherein R A is hydrogen or methyl, X is chlorine or hydrogen, R 4 is hydrogen or CH 2 NHCH 2 PO 3 H 2 , or armnoloweralkyl as defined herein, R 3 is as defined wherein with the proviso that R 3 is not OH, and R 1 and R 2 are hydrogen
  • the R 1 alkyl groups are optionally formed by contacting the above ammo acid-4 amino-sugar derivatives with an aldehyde or ketone followed by reductive amination of the resulting irrune.
  • the R 1 groups linked to the glycopeptide with an amide bond are optionally formed by reaction of the glycopeptide with the appropriate starting material containing a carboxylic acid or activated carboxylic acid moiety under known amide forming conditions
  • a second alkyl R 2 is optionally formed by contacting the amino acid-4 ammo-sugar derivatives having substituent Ri with an aldehyde or ketone followed by reductive animation of the resulting lmme.
  • the R 2 groups linked to the glycopeptide with an amide bond are optionally formed by reaction of the glycopeptide having R 1 alkyl group with the appropriate starting material containing a carboxylic acid or activated carboxylic acid moiety under known amide forming conditions
  • substitutions at R 4 are optionally introduced via Mannich reaction wherein the glycopeptide is treated with an amine and formaldehyde under basic conditions (for example, as desc ⁇ bed m The Journal of Antibiotics, Vol. 50, No. 6, p. 509-513).
  • compounds desc ⁇ bed herein are optionally made by modifying compounds having
  • R 4 is hydrogen or CH 2 NHCH 2 PO 3 H 2 , or aminoloweralkyl as defined herein
  • R 3 is as defined wherein with the proviso that R 3 is not OH, Ri and R 2 are hydrogen, by a technique selected from the group consisting of,
  • compositions described herein comprise a therapeutically effective amount of a compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) formulated together with one or more pharmaceutically acceptable carriers
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type
  • materials which can serve as pharmaceutically acceptable earners are sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil; safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols, such
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions are optionally formulated according to the known art using suitable dispersing or wetting agents and suspending agents
  • the sterile injectable preparation is optionally a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol
  • the acceptable vehicles and solvents that are optionally employed are water, Ringer's solution, U S P and isotonic sodium chloride solution
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium
  • any bland fixed oil can be employed including synthetic mono- or diglycerides
  • fatty acids such as oleic acid are used in the preparation of injectables
  • the injectable formulations can be sterilized, for example, by filtration through a bacte ⁇ al- retaimng filter, or by incorporating sterilization
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcmm phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose mannitol, and silicic acid, b) binders such as, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrohdinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentomt
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings known in the pharmaceutical formulating art They optionally contains opacifying agents and can also be of a composition that they release the active mgredient(s) only, or preferentially, in a certain part of the mtestmal tract, optionally, in a delayed manner
  • coatings and shells such as enteric coatings and other coatings known in the pharmaceutical formulating art
  • They optionally contains opacifying agents and can also be of a composition that they release the active mgredient(s) only, or preferentially, in a certain part of the mtestmal tract, optionally, in a delayed manner
  • embedding compositions which can be used include polymeric substances and waxes
  • Solid compositions of a similar type are optionally employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings known m the pharmaceutical formulating art
  • the active compound is optionally admixed with at least one inert diluent such as sucrose, lactose or starch
  • Such dosage forms optionally comprise, as is normal practice, additional substances other than inert diluents, e g , tableting lub ⁇ cants and other tabletmg aids such a magnesium stearate and microcrystalline cellulose
  • the dosage forms optionally comprise buffering agents They optionally contains opacifying agents and can also be of a composition that they release the active mgredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner
  • compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder
  • Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia Pathogenic bacteria are commonly present throughout airways down to bronchi, bronchioli and lung parenchema, particularly in terminal and respiratory bronchioles During exacerbation of infection, bacteria can also be present m alveoli
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue
  • Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of a aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ⁇
  • Aerosolization devices suitable for administration of aerosol formulations desc ⁇ bed herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ⁇
  • Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ⁇ range
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets
  • Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets
  • suitable devices are available, including, for example, AeroNeb TM and AeroDose TM
  • compounds described herein compound described herein are formulated for use as topical powders and sprays that contain, in addition to the compounds described herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances Sprays optionally contain customary propellants such as chlorofluorohydrocarbons
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium
  • Absorption enhancers can also be used to increase the flux of the compound across the skm
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel
  • bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound described herein, in such amounts and for such time as is necessary to achieve the desired result
  • a therapeutically effective amount of a compound described herein is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the seventy of the disorder, the activity of the specific compound employed, the specific composition employed, the age, body weight, general health, sex and diet of the patient, the time of administration, route of administration, and rate of excretion of the specific compound employed, the duration of the treatment, drugs used m combination or coincidental with the specific
  • SOCl 2 for thionyl chloride, PPTS for pyridmm p- toluene sulfonate, Py for pyridine, TEA for t ⁇ ethylamme, THF for tetrahydrofuran, TMSCl for t ⁇ methylsilyl chloride, TMSCF 3 for trimethyl(trifluoromethyl) silane, TPP for t ⁇ phenylphosphine, TPAP for tetra-n-propylammonium perruthenate, DMAP for 4-dirnethylarnino pyridine, TsOH for /7-toluene sulfonic acid, MsOH for methanesulfomc acid, OMs for mesylate, OTs for tosylate, OTf for triflate, Boc for tert-butoxycarbonyl, Fmoc for N-fluorenylmethoxycarbonyl, Su for succinimide, Ph for
  • glycopeptide nit ⁇ les (37 - 40) can be catalytic reduced to their corresponding aminoglycopeptides (29 - 32) in the presence of catalytic amount of Raney nickel active catalyst under hydrogen atmosphere
  • N-acylated derivatives substituted with amino acid or N alkylated ammo acid of desvancosaminyl glycopeptides 21_, 22, 29 and 30_represented by the general formula (48) wherein R A is hydrogen or methyl, n is 0 or 1 and R and Ri are previously defined, can be prepared by the treatment of the desvancosaminyl glycopeptides 21, 22, 29 and 30_with N-hydroxy succinimide ester of N-Fmoc- derivatives of the amino acid or N-alkylated amino acid followed by deprotection with 10% diethylamine in DMSO to give the desired product (48) The following is a general preparation procedure
  • adamantylamino amides derivatives (49), wherein R A is hydrogen or methyl, n is 0 or 1 and R, R 1 and X are previously defined, are prepared.
  • amino acid-4-monosaccharide glycopeptide carboxamides wherein R A is hydrogen or methyl, n is 0 or 1 , Y is hydrogen or epi-vancosammyl and R, Ri, X and R 3 are previously defined, can be prepared by the following procedure. To a mixture of 0.1 mmol of (21), (22), (23), (24), (29), (30), (31) or (32) and 1 mmol of an amine hydrochloride (R 3 NH 2 .HC1) in 5 mL of DMSO is added portion-wise triethylamine to adjust to a pH 8.5 to 9.
  • Example 56
  • N-hydroxysuccmimide (82 mg, 0.709 mmol), triethylamine (85 mg, 0.838 mmol) and l-(3-dimethylammopropyl)-3- ethylcarbodimide hydrochloride (EDCI) (136 mg, 0 709 mmol) in 10 mL of DCM was stirred at room temperature overnight Checked for completion by TLC The reaction was quenched by adding water and separated. The aqueous phase was extracted with dichloromethane.
  • EDCI l-(3-dimethylammopropyl)-3- ethylcarbodimide hydrochloride
  • mice are treated with a compound of Formula I, II, III or IV
  • Three doses of each antibiotic (30, 20, and 10 mg/kg of body weight) are tested by administering the compound in 0.1 ml of saline
  • the antibiotics are given every 12 h for 4 consecutive days
  • An infected control group is treated with saline
  • a sterile catheter is implanted in another group of animal to serve as a negative control group
  • the mice are maintained in an anesthetized state with 1 5% isoflurane gas and are imaged for at va ⁇ ous time points after inoculation by using an IVIS Imaging System Total photon emissions from defined regions of interest within the
  • Example 91 Pharmaceutical Compositions
  • a parenteral pharmaceutical composition suitable for administration by injection 50 mg of a water-soluble salt of a compound of any of Formula I, II, III or IV, is dissolved m PEG 400 and then mixed with 10 mL of 0 9% sterile saline The mixture is incorporated into a dosage unit form suitable for administration by injection
  • the compound can form a l l complex with sulfo-butylether- ⁇ -cyclodextrm (Captisol) and the complex is reconstituted with salme to a 12 % w/v Captisol solution
  • Formula I, II, III or IV is mixed with 950 mg of starch
  • the mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration
  • an oral dosage unit for such as a hard gelatin capsule, which is suitable for oral administration

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Abstract

La présente invention concerne des glycopeptides semi-synthétiques ayant une activité antibactérienne. L'invention concerne en particulier des glycopeptides semi-synthétiques produits en soumettant un glycopeptide (Composé A, Composé B, Composé H ou Composé C) à un milieu acide pour hydrolyser le fragment disaccharide de l'acide aminé 4 du glycopeptide parent afin d'obtenir le monosaccharide de l'acide aminé 4 ; en protégeant temporairement le ou les groupes amino ; en convertissant le monosaccharide en sucre aminé dérivé ; en acylant le substituant amino sur le fragment de sucre qui porte une substitution amino de l'acide aminé 4 sur ces échafaudages à l'aide de certains groupes acyle ; en convertissant le fragment acide sur le cycle macrocyclique de ces échafaudages en certains amides substitués et en enlevant le ou les groupes de protection temporaire des amino. L'invention concerne également des procédés de synthèse des composés, des compositions pharmaceutiques contenant les composés et des procédés d'utilisation des composés pour la prophylaxie et/ou le traitement de maladies, en particulier des infections bactériennes.
PCT/US2008/062483 2007-05-08 2008-05-02 Glycopeptides semi-synthétiques à activité antibactérienne Ceased WO2008140973A1 (fr)

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WO2010065174A1 (fr) * 2008-12-05 2010-06-10 Lead Therapeutics, Inc. Nouveaux glycopeptides semi-synthétiques comme agents antibactériens
WO2011140009A1 (fr) * 2010-05-04 2011-11-10 Biomarin Pharmaceutical Inc. Procédés d'utilisation de glycopeptides semi-synthétiques en tant qu'agents antibactériens
WO2017161909A1 (fr) * 2016-03-24 2017-09-28 中国医学科学院医药生物技术研究所 Dérivé de la norvancomycine et son procédé de préparation et de purification

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US20100105607A1 (en) * 2008-10-24 2010-04-29 Lead Therapeutics, Inc. Novel semi-synthetic glycopeptides as antibacterial agents
CN110312518A (zh) * 2016-12-09 2019-10-08 昆士兰大学 糖蛋白抗生物素构建体
WO2018102890A1 (fr) * 2016-12-09 2018-06-14 The University Of Queensland Constructions de visualisation

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US20050075483A1 (en) * 1998-07-14 2005-04-07 Trustees Of Princeton University Glycopeptide antibiotics, combinatorial libraries of glycopeptide antibiotics and methods of producing same
WO2004019970A2 (fr) * 2002-08-30 2004-03-11 K.U. Leuven Research And Development Derives antibiotiques de glycopeptides
WO2006057303A1 (fr) * 2004-11-29 2006-06-01 National University Corporation Nagoya University Derives monomeres antibiotiques de glycopeptides
US20070021328A1 (en) * 2005-02-28 2007-01-25 Chiron Corporation Semi-synthetic rearranged vancomycin/desmethyl-vancomycin-based glycopeptides with antibiotic activity

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010065174A1 (fr) * 2008-12-05 2010-06-10 Lead Therapeutics, Inc. Nouveaux glycopeptides semi-synthétiques comme agents antibactériens
JP2012510999A (ja) * 2008-12-05 2012-05-17 ビオマリン プハルマセウトイカル インコーポレイテッド 抗菌薬としての新規の半合成糖ペプチド
WO2011140009A1 (fr) * 2010-05-04 2011-11-10 Biomarin Pharmaceutical Inc. Procédés d'utilisation de glycopeptides semi-synthétiques en tant qu'agents antibactériens
WO2017161909A1 (fr) * 2016-03-24 2017-09-28 中国医学科学院医药生物技术研究所 Dérivé de la norvancomycine et son procédé de préparation et de purification

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