WO2002085867A1 - Antibiotiques aa-896 - Google Patents

Antibiotiques aa-896 Download PDF

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Publication number
WO2002085867A1
WO2002085867A1 PCT/US2002/013024 US0213024W WO02085867A1 WO 2002085867 A1 WO2002085867 A1 WO 2002085867A1 US 0213024 W US0213024 W US 0213024W WO 02085867 A1 WO02085867 A1 WO 02085867A1
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WO
WIPO (PCT)
Prior art keywords
hydroxy
pyrimidinyl
furanyl
methyl
dioxo
Prior art date
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PCT/US2002/013024
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English (en)
Inventor
Yang-I Lin
Zhong Li
Gerardo Delacruz Francisco
Leonard Alexander Mcdonald
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Wyeth Holdings Corporation
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Publication date
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Publication of WO2002085867A1 publication Critical patent/WO2002085867A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • 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

Definitions

  • the present invention relates to novel compounds of AA-896 which exhibit antibacterial activity. BACKGROUND OF THE INVENTION
  • Isolated Liposidomycins A-(l), A-(ll), A-(lll) and A-(IV) are also reported to have antibacterial activity (Kimura, K.; Ikeda, Y.; Kagami, S.; Yoshihara, M., J. Antibiotics, 1998, 51, 1099-1 104. and other references herein).
  • Liposidomycins A, B and C using their chemical degradation products has been reported (Ubukata, M.; Kimura, K.; Isono, K.; Nelson, CO; Gregson, J.M.; McClosky, J.A., J.Org.Chem., 1992, 57, 6392- 6403).
  • Liposidomycin class compounds are further reported (JP05078385) and are derivatives of 2-methylamino-3-(5-aminomethyl-4-hydroxy-3-hydroxy-tetrahydro-fura- 2-yloxy)-3-[3,4-dihyoxy-5-(2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl)tetrahydro-2- furanyl]propanoic acid or the degraded products of 2-methylamino-3-(5-aminomethyl- 4-hydroxy-3-hydroxy-tetrahydro-fura-2-yloxy)-3-[3,4-dihyoxy-5-(2,4-dioxo-3,4- dihydro-1 (2H)-pyrimidinyl)tetrahydro-2-furanyl]-propanoic acid.
  • This invention is concerned with a new series of nucleoside peptide antibiotics of AA-896.
  • This invention is concerned with novel nucleoside peptide antibiotics of AA- 896 which have antibacterial activity; with methods of treating infectious disease in mammals employing these novel nucleoside peptide antibiotics; with pharmaceutical compositions containing these novel nucleoside peptide antibiotics and processes for the production of novel nucleoside peptide antibiotics of the invention.
  • Compounds according to the invention comprise compounds of the formula
  • Rj is H, aryl, alkyl (d-Ca,), -CH 2 -aryl, -C(O)alkyl(CrC 2 o), C(O)NHalkyl(C ⁇ -C 20 ), or -C(O)NHaryl;
  • R 2 is H, alkyl (C C2o), -CH 2 aryl, or -C(O)alkyl(C C 20 );
  • R 3 is -OH
  • R 2 and R 3 may optionally be taken together to form a moiety
  • R 4 is alkyl (CrC 2 o), or aryl; provided R-i and R are not H when R 3 is -OH
  • R 2 is H, alkyl (C-C ⁇ ), or -CH 2 aryl;
  • Rj is H, -C(O)alkyl(CrC 16 ), or -C(O)aryl when R 2 and R 3 are taken together to form a moiety
  • R 4 is alkyl(C ⁇ -C 16 ), or aryl.
  • Specifically preferred compounds of the invention are the following compounds or a pharmaceutically acceptable salt thereof:
  • Halogen as used herein means fluoro, chloro, bromo and/or iodo.
  • Alkyl as used herein means a branched or straight chain radical having from 1 to 20 (preferably 1 to 16) or preferably (1 to 12)carbon atoms optionally substituted with morpholino where the morpholino nitrogen atom may optionally be alkylated with alkyl of 1 to 6 carbon atoms forming a quaternary salt.
  • exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl, also optionally substituted, as well as perfluoroalkyl.
  • Aryl as used herein means a homocyclic or polycyclic aromatic radical, having 6 to 20 carbon atoms independently substituted with one to three substituents selected from the group of alkyl, halogen, cyano, nitro, hydroxy, , amino, alkylamino, dialkylamino, or alkoxy. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, fluorenyl, and anthracenyl, optionally substituted with one to three substituents.
  • Example 12 in D2O at 300 MHz Fig. 10.
  • Proton NMR spectrum of Example 14 in D2O at 300 MHz Fig. 11.
  • Proton NMR spectrum of Example 16 in D2O at 300 MHz Fig. 12.
  • Proton NMR spectrum of Example 18 in D2O at 300 MHz Fig. 13.
  • Proton NMR spectrum of Example 20A in D2O at 300 MHz Fig. 16 Proton NMR spectrum of Example 20B in D2O at 300 MHz Fig. 17
  • the compounds of the invention are prepared according to the following reaction schemes.
  • compounds of this invention encompasses all crystalline forms.
  • compounds of the invention may be obtained as pharmaceutically acceptable salts which are those derived from such organic and inorganic acids as: acetic, trifluoroacetic, lactic, citric, tartaric, formate, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
  • compounds of the invention may form calcium, potassium, magnesium, or sodium salts.
  • the pharmaceutically acceptable salts of compounds of the invention are prepared using conventional procedures. Compounds of the invention have centers of asymmetry. The compounds of the invention may, therefore, exist in at least two and often more stereoisomeric forms.
  • the present invention encompasses all stereoisomers whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixtures of enantiomers as well as the diastereomeric mixtures of isomers.
  • the absolute configuration of any substantially pure compound may be determined by any suitable method including conventional X-ray crystallography.
  • the present invention accordingly provides a pharmaceutical composition which comprises a compound of the invention or a mixture thereof in combination or association with a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition which comprises an effective amount of compounds of the invention or a mixture thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides methods which may be used in treating bacterial infections in warm blooded animals which comprise providing to said animals an antibacterially effective amount of a compound of the invention or a mixture thereof.
  • Example 1 through Example 20 The in vitro antibacterial activity of Example 1 through Example 20 is determined against a spectrum of Gram-positive and Gram-negative bacteria by a standard broth dilution method. Serial dilution of the compounds are made in Mueller-Hinton broth and inoculated with a bacterial suspension. The lowest concentration of compound that inhibited the growth of a bacterial strain after 18 hours of incubation at 35 °C is reported as the minimal inhibitory concentration (MIC) for that strain. The results are given in Table 1.
  • the MurG biochemical assay utilizes S. epidermides membranes to catalyze the late steps in cell wall biosynthesis including MraY, the phospho-MurNAc pentapeptide translocase and MurG, the UDP-N-Acetylglucosaminyl transferase.
  • MraY the phospho-MurNAc pentapeptide translocase
  • MurG the UDP-N-Acetylglucosaminyl transferase.
  • the following procedure is adapted from the method described by Mengin-Lecreaulx, et al (J. Bacteriol 173(15) 4625-4636, 1991 ). In this procedure, the formation of Lipid II is assessed using radiolabeled UDP-N-Acetylglucosamine.
  • S. epidermides membranes, compound, UDP-MurNAc pentapeptide, and [ 14 C]-UDP- N-Acetylglucosamine were incubated at room temperature for 30 min. The reaction was terminated by boiling in a water bath for 1 minute. 2 ⁇ l samples of each reaction are analyzed by TLC. The samples are spotted onto K6 silica plates and chromatographed in Isobutyric Acid:1 M NH 4 OH (5:3). The plates are exposed to film and the inhibition of Lipid II formation can be monitored by comparing the sample area to the control area.
  • Compounds of the invention derive their utility from their antibacterial activity.
  • these compounds may be used in the suppression of bacterial infections, as a topical antibacterial agent and as a general disinfectant for laboratories.
  • the compounds of this invention may be administered in the form of conventional pharmaceutical compositions appropriate for the intended use.
  • Such compositions may be formulated so as to be suitable for oral, parenteral or topical administration.
  • the compounds of the invention may be combined in admixture with a nontoxic pharmaceutical carrier, which carrier may take a variety of forms, depending on the form of preparation desired for administration, ie. oral, parenteral, or topical.
  • the compounds of the invention when employed for the above utility, they can be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example from about 10 to 50% of sugar, and elixirs containing, for example from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium.
  • pharmaceutically acceptable carriers for example, solvents, diluents and the like
  • Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the compounds of the invention in combination with the carrier, more usually between about 5% and 60% by weight.
  • An antibacterially effective amount of compounds of the invention from about 0.5 mg/kg of body weight to about 200.0 mg/kg of body weight should be administered one to five times per day via any topical routes of administration including but not limited to oral, parenteral (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically ⁇ acceptable carriers, adjuvants and vehicles.
  • the antibacterially effective amount of the compounds of the invention may be administered at a dosage and frequency without inducing side effects commonly experienced with conventional antibiotic therapy which could include hypersensitivity, neuromuscular blockade, vertigo, photosensitivity, discoloration of teeth, hematologic changes, gastrointestinal disturbances, ototoxicity, and renal, hepatic, or cardiac impairment. Further the frequency and duration of dosage may be monitored to substantially limit harmful effects to normal tissues caused by administration at or above the antibacterially effective amount of the substantially pure compounds of the invention.
  • active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
  • Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
  • compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules. Oral administration of the compound is preferred.
  • the compounds of the invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microrganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
  • the reaction mixture is stirred overnight (the reaction is monitored by mass spectroscopy (MS)). After the reaction is complete, the volatile materials are removed under reduced pressure. N,N-dimethylformamide (DMF) (3 ml) is added to the residue, followed by addition of 13.0 mg (95 ⁇ mol) of 4-f luorophenyl isocyanate. The reaction mixture is stirred at room temperature for 50 hours (the reaction was monitored by MS). The volatile materials are removed under reduced pressure to afford a residue to which is added 5 ml of 0.5% trifluoroacetic acid (TFA) in a 1 :1 mixture of water and p-dioxane. The mixture is stirred at room temperature for 2 hours.
  • TFA trifluoroacetic acid
  • Example 6 16-((R)- ⁇ [(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2- furanyl]oxy ⁇ (2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3,4- dihydroxytetrahydro-2-furanyl ⁇ methyl)-15-benzyl-9-(1-hydroxy-2-methylpropyl)- 6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15- pentaazaheptadecane-1 ,17-dioic acid To a solution of 56.8 mg (60 ⁇ mol) 16-( ⁇ [5-(aminomethyl)-4-hydroxy-3- methoxytetrahydro-2-furanyl]oxy ⁇ 5-[2,4-dio
  • reaction mixture is stirred for 48 hours (the reaction is monitored by MS). After the reaction is complete, the volatile materials are removed under reduced pressure. N,N-Diemthylformamide (4 ml) is added to the residue, followed by addition of 12.3 mg (72 ⁇ mol) of benzyl bromide. The reaction mixture is stirred at room temperature overnight (the reaction is monitored by MS). The volatile materials are removed under reduced pressure to a residue to which is added 5 ml of 0.5% TFA in a 1 :1 mixture of wate ⁇ p-dioxane and the mixture is stirred at room temperature for 2 hours. The reaction is monitored by MS and the desired product identified by LC/MS.
  • reaction mixture is stirred for 2 days (the reaction is monitored by MS). After the reaction is complete, the volatile materials are removed under reduced pressure. N,N-Dimethylformamide (3 ml) is added to the residue, followed by addition of 14.4 mg (78 ⁇ mol) of dodecyl aldehyde.
  • the reaction mixture is kept at 70°C for 0.5 hour, followed by addition of 78 ⁇ mol of sodium cyanoborohydride (NaBH 3 CN), and the reaction mixture is heated at 70°C (oil-bath) for an additional 2 hours (the reaction is also monitored by MS).
  • NaBH 3 CN sodium cyanoborohydride
  • the volatile materials are removed under reduced pressure to a residue to which is added 5 ml of 0.5% trifluoroacetic acid in a 1 :1 mixture of water:p-dioxane and the reaction mixture stirred at room temperature for 2 hours.
  • the reaction is monitored by MS and the desired product is identified by LC/MS. After concentration of the reaction mixture to about one ml, 21 mg of the desired product is separated by preparative HPLC.
  • reaction mixture is stirred for 2 days and monitored by MS. After the reaction is completion, the reaction mixture is filtered, and washed with methanol. The volatile materials are removed under reduced pressure to a residue to which is added N,N-Dimethylformamide (3 ml) followed by additon of 66 mg (245 ⁇ mol) of 12-(4-morpholinyl)dodecanal (see examples 21 & 22). After stirring at room temperature for two hours, 46.8 mg of sodium triacetoxyborohydride and 4.2 mg of acetic acid are added.
  • Example 10 4-[13-((2R)-2- ⁇ [(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2- furanyl]oxy ⁇ -1-carboxy-2- ⁇ (2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)- pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl ⁇ ethyl)-26-carboxy-19-(1- hydroxy-2-methylpropyl)-22-(2-iminohexahydro-4-pyrimidinyl)-27-methyl-
  • Example 12 14-[5-((R)- ⁇ (2S,5R)-5-[2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3,4- dihydroxytetrahydro-2-furanyl ⁇ [(5R)-4-hydroxy-3-methoxy-5-( ⁇ [(4- fluoroanilino)carbonyl]amino ⁇ methyl)tetrahydro-2-furanyl]oxy ⁇ methyl)-3-(4- fluorophenyl)-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2- iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11- tetraazatetradecan-1-oic acid
  • the title compound is prepared by the procedure of Example 1 1 ,
  • Example 14 14-[5-((R)- ⁇ (2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3,4- dihydroxytetrahydro-2-furanyl ⁇ [(3R,4S,5R)-5- ( ⁇ [(hexylamino)carbonyl]amino ⁇ methyl)-4-hydroxy-3-methoxytetrahydro-2- furanyl]oxy ⁇ methyl)-3-hexyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2- methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo- 3,5,8,11 -tetraazatetradecan-1 -oic acid
  • the title compound is prepared by the procedure of Example 11 , using 47.3 mg (50 ⁇ mol) of
  • Example 16 16-((R)- ⁇ (2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3,4- dihydroxytetrahydro-2-furanyl ⁇ [(3R,4S,5R)-5-
  • Examples 19a and 19b 16-((R)-[((3R,4S,5R)-5- ⁇ [([1,1'-Biphenyl]-4-ylmethyl)amino]methyl ⁇ -4-hydroxy-3- methoxytetrahydro-2-furanyl)oxy] ⁇ (2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)- pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl ⁇ methyl)-9-(1-hydroxy-2- methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-
  • Example 19a After stirring for 5 minutes, 0.04 ml of methanolic hydrochloric acid is added. The reaction mixture is then stirred for 0.5 hour and monitored by MS. The solvent is removed under reduced pressure to give a yellow gum. The desired products are separated by preparative HPLC to give 3.0 mg (12 % yield) of Example 19a as a white solid and 4.0 mg (15% yield, L17742-171 -2) of Example 19b also as a white solid.
  • Example 20a After stirring for 5 minutes, 0.04 ml of methanolic hydrochloric acid is added. The reaction mixture is then stirred for 0.5 hour. The reaction is monitored by MS. The solvent is removed under reduced pressure to give a yellow gum. The desired products are separated by preparative HPLC to give 15 mg (26 % yield) of Example 20a as a white solid and 2.5 mg (4% yield) of Example 20b as a white solid.
  • Example 24 16-((R)-( ⁇ (3R,4S,5R)-5-[(Acetamido)methyl]-4-hydroxy-3-methoxytetrahydro-2- furanyl ⁇ oxy) ⁇ (2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3,4- dihydroxytetrahydro-2-furanyl ⁇ methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2- iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11 ,15- pentaazaheptadecane-1 ,17-dioic acid

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Abstract

L'invention concerne des composés d'antibiotiques AA896 représentés par la formule (I). Dans cette formule, R1 représente H, aryle, (C1-C20)alkyl, -CH2-aryl, -C(O)alkyl(C1-C20), -C(O)NHalkyl(C1-C20), ou -C(O)NHaryl; R2 représente H, (C1-C20)alkyl, -CH2aryl, (C1-C20)alkyl ou -C(O)alkyl(C1-C20); R3 représente -OH; R2 et R3 peuvent éventuellement être pris ensemble pour former une fraction (II); R4 représente (C1-C20)alkyl, ou aryle. L'invention concerne également un sel pharmaceutiquement acceptable de ces composés.
PCT/US2002/013024 2001-04-25 2002-04-25 Antibiotiques aa-896 WO2002085867A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US28629701P 2001-04-25 2001-04-25
US60/286,297 2001-04-25
US29014001P 2001-05-10 2001-05-10
US60/290,140 2001-05-10

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1783908A3 (fr) * 2005-10-27 2009-03-18 Realtek Semiconductor Corp. Générateur d'une séquence de bruit pseudo-aléatoire en forme spectrale et procédé correspondant
WO2010098365A1 (fr) * 2009-02-25 2010-09-02 塩野義製薬株式会社 Antibiotique de type nucléoside
US7994140B2 (en) 2002-10-11 2011-08-09 Alchemia Limited Classes of compounds that interact with GPCRs
US8222381B2 (en) * 2002-08-08 2012-07-17 Alchemia Limited Derivatives of monosaccharides for drug discovery
US8223819B2 (en) 2005-10-27 2012-07-17 Realtek Semiconductor Corp. Spectrally shaped pseudo-random noise sequence generator and method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DINI ET AL.: "Synthesis of analogues of the O-b-D_Ribofuranosyl nucleotide moiety of liposidomycins: Part 2: role of hydroxyl groups upon the inhibition of MraY", BIORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11, 2001, pages 533 - 536, XP004230052 *
DINI ET AL.: "Synthesis of nucleoside moiety of liposidomycins: elucidation of pharmacophore of this family of Mra inhibitors", BIORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 10, 2000, pages 1839 - 1841, XP004216012 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8222381B2 (en) * 2002-08-08 2012-07-17 Alchemia Limited Derivatives of monosaccharides for drug discovery
US7994140B2 (en) 2002-10-11 2011-08-09 Alchemia Limited Classes of compounds that interact with GPCRs
EP1783908A3 (fr) * 2005-10-27 2009-03-18 Realtek Semiconductor Corp. Générateur d'une séquence de bruit pseudo-aléatoire en forme spectrale et procédé correspondant
US8223819B2 (en) 2005-10-27 2012-07-17 Realtek Semiconductor Corp. Spectrally shaped pseudo-random noise sequence generator and method thereof
WO2010098365A1 (fr) * 2009-02-25 2010-09-02 塩野義製薬株式会社 Antibiotique de type nucléoside

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