WO2007040289A1 - Inhibiteur de la déformylase, procédé de préparation de celui-ci et composition le comprenant - Google Patents

Inhibiteur de la déformylase, procédé de préparation de celui-ci et composition le comprenant Download PDF

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Publication number
WO2007040289A1
WO2007040289A1 PCT/KR2005/003288 KR2005003288W WO2007040289A1 WO 2007040289 A1 WO2007040289 A1 WO 2007040289A1 KR 2005003288 W KR2005003288 W KR 2005003288W WO 2007040289 A1 WO2007040289 A1 WO 2007040289A1
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methyl
formula
butyl
oxo
compound
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PCT/KR2005/003288
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English (en)
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Bong-Jin Lee
Seung-Kyu Lee
Kwang-Hyun Choi
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Promeditech Inc.
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Priority to PCT/KR2005/003288 priority Critical patent/WO2007040289A1/fr
Publication of WO2007040289A1 publication Critical patent/WO2007040289A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/14—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a novel deformylase inhibitor, and more particularly to a novel deformylase inhibitor having excellent activity or a pharmaceutically acceptable salt thereof, a preparation process thereof, and a pharmaceutical composition comprising the same as an active ingredient.
  • Deformylase is metallopeptidase, which is found in prokaryotes such as bacteria.
  • the synthesis of proteins in prokaryotes is initiated by N-formyl methionine (fMet). After the initiation of protein synthesis, the formyl group is removed by deformylase. It is known that such activity is essential for the maturation of proteins, and thus deformylase is essential for the growth of cells (Chang et al., J. Bacteriol. 171: 4071-4072(1989); Meinnel T, Blanquet S, J. Bacteriol. 176(23): 7387-90(1994); Mazel D et. al., EMBO J. 13(4): 914-23(1994)). However, the initiation of protein synthesis in prokaryotes is independent on fMet, and thus, when an inhibitor of deformylase is developed, it will be useful as an antibacterial agent having a broad spectrum of activity.
  • fMet N-formyl methionine
  • WO 02/102790 N-formyl hydroxylamine derivatives
  • WO 01/44179 succinate derivatives
  • WO 01/44178 urea derivatives
  • WO 01/85170 peptide derivatives
  • the present invention has been developed based on said prior art, and provides a novel deformylase inhibitor having a non-peptide bond.
  • Another object of the present invention is to provide a process for preparing the deformylase inhibitor.
  • Still another object of the present invention is to provide a pharmaceutical composition comprising the deformylase inhibitor as an active ingredient.
  • the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
  • R is a straight-chain or branched C -C alkyl, or a C -C alkyl substituted with C -C cycloalkyl or heteroaryl,
  • R ,2 i-s hydrogen, straight-chain or branched C -C alkyl, or benzyl
  • pyridinyl or oxidized pyridinyl in which said phenyl, pyridinyl or oxidized pyridinyl may be substituted with 1-3 substituents selected from the group consisting of C -C alkyl, C -C alkoxy, hydroxy, halogen, cyano, nitro, acetyl, phenyl, trifluoromethyl, tri-
  • R , R and R can be substituted with any one selected from the group consisting of hydrogen, C -C alkyl, C -C alkoxy, hydroxy, halogen, cyano, nitro, acetyl, phenyl, trifluoromethyl, trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, and benzyl.
  • Preferred examples of the compound according to the present invention are as follows: [19] 1) N- ⁇ (2R,4S)-2-butyl-4-[3-(5-fluoro-pyridin-2-yl)-ureido] - 5-methyl-3-oxo-hexyl ⁇ -N-hydroxy-foraiamide; [20] 2) N- ⁇ (2R,4S)-2-butyl-4-[3-(5-fluoro-l-oxy-pyridin-2-yl)-ureido] -
  • the compounds according to the present invention can be in the form of pharmaceutically acceptable salts, hydrates or solvates.
  • pharmaceutically acceptable salts which can be applied to the inventive compound, include hydrochloride, bromate, sulfate, methylsulfonate, p-toluenesulfonate, phosphate, acetate, citrate, succinate, lactate, tartrate, furmate, maleate, sodium salt, potassium salt, magnesium salt, and calcium salt.
  • inventive compounds contain a chiral carbon atom, and thus can be in the form of racemate or optical isomers. Accordingly, the inventive compounds include all these racemates and optical isomers.
  • the present invention provides a process for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula 1 is prepared by removing the hydroxy-protecting group of a compound of Formula 3, synthesized from a compound of Formula 4:
  • R , R and R are as defined above, and Y is the hydroxy-protecting group.
  • the compound of Formula 4 can be prepared by allowing a compound of Formula 6 or its salt to react with -HNR to prepare a compound of Formula 5 and then allowing the compound of Formula 5 to react with YONH .
  • reaction of the compound of Formula 5 with YONH can be carried out by stirring the reaction mixture under reflux in an organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylsulfoxide or toluene or without using any solvent.
  • organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylsulfoxide or toluene or without using any solvent.
  • R and R are as defined above, and X is chloro or imidazole.
  • the reaction of the compound of Formula 6 with HNR can be carried out by stirring the reaction mixture in an organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylsulfoxide or toluene.
  • the compound of Formula 6 is prepared by allowing a salt (e.g., hydrochloride or trifluoroacetate) of a compound of Formula 7 to react with triphosgen or l,l'-carbonyldiimidazole.
  • the reaction in this step can preferably be carried out in the presence of a base such as triethylamine, diisopropylethylamine or N- methylmorpholine, and solvents usable in this reaction include organic solvents, such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylsulfoxide, and toluene.
  • a base such as triethylamine, diisopropylethylamine or N- methylmorpholine
  • solvents usable in this reaction include organic solvents, such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylsulfoxide, and toluene.
  • R and R are as defined above, and Z is an amino-protecting group.
  • a preferred example of the amino-protecting group Z is t-butoxycarbonyl.
  • the benzyl group of the compound of Formula 8 is removed by hydrogenation in the presence of palladium/carbon, and the resulting material is stirred with piperidine/ formaldehyde under reflux in a lower alcohol solvent, thus preparing an exomethylene compound.
  • the amino-protecting group of the exomethylene compound is removed in a condition of hydrochloric acid or trifluoroacetic acid, thus preparing the salt of Formula 7.
  • the compound of Formula 8 can be prepared by allowing the compound of Formula 9 to react with a straight-chain or branched C -C alkyl substituted with alkyl sulfate or halogen, or a C -C alkyl compound substituted with C -C cycloalkyl or heteroaryl, in the presence of a base such as potassium carbonate.
  • the compound of Formula 9 can be prepared by allowing the compound of Formula 10 to react with Meldrum's acid, dicyclohexylcarbodiimide and dimethy- laminopyridine and then stirring the reaction intermediate with benzyl alcohol under reflux in a toluene or benzene solvent.
  • the present invention encompasses an antibacterial composition
  • an antibacterial composition comprising a therapeutically effective amount of the compound of Formula 1 or a salt thereof, together with a pharmaceutically acceptable carrier.
  • the inventive composition can be administered to infected patients or animals, or can be used in infected skin to treat bacterial infection. Also, it can be used as a component of antibacterial cleansing or disinfecting agents.
  • the inventive composition can be administered orally or parenterally.
  • the oral composition can be in various forms such as tablets, capsules, powders, granules, liquids, suspensions and gels, and can contain conventional additives such as excip ients, disintegrants or lubricants.
  • the additives include conventional excipients such as syrup, gum Arabic, gelatin, sorbitol, lactose, glucose, corn starch, calcium phosphate, glycine, magnesium stearate, talc, polyethylene glycol, silica, potato starch, sodium lauryl sulfate and so on, and general flavoring or coloring agents.
  • the parenteral composition e.g., injection solution
  • the parenteral composition can be an isotonic solution, and can also be sterilized and/or contain conventional additives such as preservatives and stabilizers.
  • composition according to the present invention can be administered at a dose of about 7-35 g/day to an adult average patient (weighing about 70 kg) for the purpose of antibacterial treatment, but said dose can be changed depending on the type and condition of disease.
  • each unit dosage form can contain about 0.7 mg-2.8 g of the compound according to the present invention together with a pharmaceutically acceptable carrier.
  • Step 1 (SV4-t-butoxycarbonylamino-5-methyl-3-oxo-hexanoic acid benzyl ester
  • the concentrate was dissolved in toluene, benzyl alcohol was added thereto, and the solution was stirred at 80 0 C for 4 hours.
  • the reaction solution was concentrated in a vacuum and purified by silica gel column chromatography to afford 0.39 g (48.1% yield) of the title compound.
  • Step 2 (SV4-t-butoxycarbonylamino-2-butyl-5-methyl-3-oxo-hexanoic acid benzyl ester
  • Step 3 ((S)-l-isopropyl-3-methylene-2-oxo-heptyl)-carbamic acid t-butyl ester [87] To an ethanol (94 ml) solution of
  • the reaction solution was concentrated in a vacuum, and the concentrate was dissolved in ethyl ester, and then washed with brine saturated with IN HCl aqueous solution. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. The concentrate was purified by silica gel column chromatography to afford 3.3 g (61% yield) of the title compound.
  • step 4 1,1-carbonylimidazole (0.64 g, 3.93 mmol) and triethylamine (0.4 ml, 2.88 mmol) were added, and stirred at room temperature for 4 hours.
  • the reaction solution was washed with water, and the separated organic layer was dried over anhydrous magnesium sulfate and then concentrated in a vacuum.
  • the concentrate was purified by silica gel column chromatography to afford 0.26 g (35.7%) of the title compound.
  • Step 8 s N- benzyloxy-N-((2R.4SV2-butyl-5-methyl-4-r3-(5-fluoro-pyridin-2-ylVureidol-3-oxo-he xyl)-formamide
  • Example 2 N4f2R.4SV2-hutyl-4-r3-f5-fluoro-l-oxy ⁇ yridin-2-ylVureidol - 5-methyl-3-oxo-hexyl ⁇ -N-hvdroxy-formainide
  • Step I N- benzyloxy-N-((2R.4SV2-butyl-4-r3-(5-fluoro-l-oxy-pyridin-2-ylVureidol-5-methyl-3- oxo-hexyl ⁇ -formamide
  • Step 2 N-((2R.4SV2-butyl-4-r3-(5-fluoro-l-oxy-pyridin-2-ylVureidol -
  • Example 10 N-rf2R.4SV2-hutyl-4-G-hutyl-ureidoV5-methyl-3-oxo-hexyll -
  • Example 14 N- ir2R.4SV2-butyl-5-methyl-4-r3-r5-methyl-l-oxy-pyridin-2-ylVureidol-3-oxo-hexyl l-N-hydroxy-formamide [140] 1 H-NMR (CDCl ) ⁇ 0.59-1.01 (m, 9H), 1.26-1.60 (m, 6H), 2.30 (m, 4H), 3.30-3.93
  • a deformylase-producing bacterial strain (Novagen, USA, cat. no. 69041) was inoculated into 30 ml of LB medium (8 g/1 trypton, 5 g/1 yeast extract, 5 g/1 NaCl, 2.5 ml IN NaOH) containing ampicillin at 50 0 C, and was cultured at 37 0 C.
  • the culture medium was inoculated into 3 L of the same LB medium, and when O.D (660nm) reached 0.5, 1 mM isopropyl- ⁇ -D-thiogalactopyranoside was injected into the medium, and the expression thereof was induced.
  • the culture medium was centrifuged to harvest cell pellets, which were then stored at -80 0 C for 30 minutes, resuspended in phosphate buffer saline, and disrupted with ultrasonic waves at intervals of 1-sec pulse and 8-sec pause. Then, the cell medium was ultracentrifuged to collect the supernatant, which was then attached to an adsorption column and isolated with lysis buffer. Among the isolated fractions, a fraction containing peptide deformylase was confirmed with SDS-PAGE and eluted using gel chromatography.
  • a zymogen stabilizer a buffer containing 5 mM NiCl was used, and whether the zymogen was purified was examined using SDS-PAGE and dynamic light scattering.
  • the purified zymogen was stored at -80 0 C before use.
  • each of the compounds prepared in the Examples above was dissolved in dimethyl- sulf oxide to a concentration of 2 mM, and 7 D of the solution was dispensed onto a microtiter plate.
  • Deformylase was diluted in a buffer solution (5OmM HEPES, pH7.0, 1OmM NaCl, 5mM NiCl , 0.1% Triton X-100) to a concentration of 250 nM and dispensed onto the microtiter plate.
  • a buffer solution 5OmM HEPES, pH7.0, 1OmM NaCl, 5mM NiCl , 0.1% Triton X-100
  • each of the compounds prepared in the Examples was diluted at a dilution ratio of 7/2 using a serial dilution method, and the final amount in each well was adjusted to 50D.
  • Haemophilus influenzae and Moraxella catarrhalis were inoculated into a culture medium (supplemented with 37 g/1 brain heart infusion (Difco, USA), 10 mg/1 NAD, and 5 mg/1 hemin) and cultured for 24 hours and 48 hours, respectively, and Streptococcus pneumoniae was inoculated into a GC medium containing 5% horse serum and cultured for 48 hours.
  • the cells were diluted to a concentration of 1 x 10 CFU/ml and inoculated onto a microtiter plate, and the minimal inhibitory concentrations (MIC) of the compounds, which inhibited the visible growth of the bacteria, were determined after 24 hours for Haemophilus influenzae and 48 hours for Moraxella catarrhalis and Streptococcus pneumoniae. All the culture processes of the bacteria were conducted at 37 0 C in 5% CO .
  • the minimal inhibitory concentrations of the inventive compounds are shown in Table 2 below.
  • the compound according to the present invention or a pharmaceutically acceptable salt thereof has excellent deformylase inhibitory effects, and thus is effective against bacteria having resistance to prior antibacterial agents and is useful as an antibacterial agent having a broad spectrum of activity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne un nouvel inhibiteur de la déformylase ayant une excellente activité ou un sel de celui-ci acceptable sur le plan pharmaceutique, un procédé de préparation dudit inhibiteur et une composition pharmaceutique le comprenant en tant qu’ingrédient actif. L’inhibiteur de la déformylase décrit est efficace contre les bactéries résistantes à des agents antibactériens plus anciens et a un large spectre d’activité.
PCT/KR2005/003288 2005-10-05 2005-10-05 Inhibiteur de la déformylase, procédé de préparation de celui-ci et composition le comprenant WO2007040289A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009088192A2 (fr) 2008-01-04 2009-07-16 Lg Life Sciences Ltd. Dérivés d'indole et d'indolazole possédant un effet de conservation de cellules, de tissus et d'organes
WO2015032621A1 (fr) * 2013-09-06 2015-03-12 Sandoz Ag Synthèse de cétones époxy peptidiques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085170A1 (fr) * 2000-05-05 2001-11-15 Smithkline Beecham Corporation Inhibiteurs de peptide deformylase
WO2002070540A2 (fr) * 2001-03-01 2002-09-12 Smithkline Beecham Corporation Inhibiteurs de peptide deformylase (pdf)
WO2003002522A1 (fr) * 2001-04-05 2003-01-09 Smithkline Beecham Corp Inhibiteurs de peptide deformylase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085170A1 (fr) * 2000-05-05 2001-11-15 Smithkline Beecham Corporation Inhibiteurs de peptide deformylase
WO2002070540A2 (fr) * 2001-03-01 2002-09-12 Smithkline Beecham Corporation Inhibiteurs de peptide deformylase (pdf)
WO2003002522A1 (fr) * 2001-04-05 2003-01-09 Smithkline Beecham Corp Inhibiteurs de peptide deformylase

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009088192A2 (fr) 2008-01-04 2009-07-16 Lg Life Sciences Ltd. Dérivés d'indole et d'indolazole possédant un effet de conservation de cellules, de tissus et d'organes
WO2015032621A1 (fr) * 2013-09-06 2015-03-12 Sandoz Ag Synthèse de cétones époxy peptidiques
CN105518019A (zh) * 2013-09-06 2016-04-20 桑多斯股份公司 肽环氧基酮的合成

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