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WO1999033839A1 - Composes derives du cepheme, procede de production associe et composition antibacterienne les contenant - Google Patents

Composes derives du cepheme, procede de production associe et composition antibacterienne les contenant Download PDF

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Publication number
WO1999033839A1
WO1999033839A1 PCT/KR1998/000463 KR9800463W WO9933839A1 WO 1999033839 A1 WO1999033839 A1 WO 1999033839A1 KR 9800463 W KR9800463 W KR 9800463W WO 9933839 A1 WO9933839 A1 WO 9933839A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
cephem
amino
carboxylic acid
oxo
Prior art date
Application number
PCT/KR1998/000463
Other languages
English (en)
Inventor
Yeo Hong Yoon
Koun Ho Lee
Seok Bum Song
Ho Sung Whang
Kwang Hyuk Lee
Je Hak Kim
Dal Hyun Kim
Young Gi Kim
Jin Ah Kang
Youn Ha Lee
Original Assignee
Cheil Jedang Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1019980050525A external-priority patent/KR100294871B1/ko
Application filed by Cheil Jedang Corporation filed Critical Cheil Jedang Corporation
Priority to AU16940/99A priority Critical patent/AU1694099A/en
Publication of WO1999033839A1 publication Critical patent/WO1999033839A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to novel cephem derivatives in which known phenyl oxazolidinone derivatives are chemically combined with cephem, a process for producing the cephem derivatives, and a pharmaceutical antibacterial composition containing the cephem derivatives.
  • pyridine-substituted phenyl oxazolidinone derivatives disclosed in the above patents are effective against Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae. However, they are not active against Gram-negative bacteria such as Escherichia coli, Klebsiella, Proteus, and Seratia mar censes. Moreover, they cannot be administered as an injection solution because their free amine forms are little soluble.
  • the inventors have intensively studied to develop new antibacterial agents which have effective and excellent activity against Gram-negative bacteria and Gram-positive bacteria, and which are soluble so that they can be used as an injection solution.
  • the structurally new compounds were produced by chemically reacting known antibacterial oxazolidinone compounds with cephem compounds. They were found to be potently active against Gram-negative bacteria as well as Gram-positive bacteria.
  • the present invention provides compounds of the formula I:
  • R is hydrogen, or lower alkyl optionally substituted with carboxylic acid or inorganic cation salt thereof or protected carboxylic acid, and the alkoxyimino is a syn isomer;
  • R2 is hydrogen, fluorine, chlorine or methoxy and can be same or different;
  • R3 is hydrogen, or lower alkyl optionally substituted with carboxy or inorganic cation salt thereof, amino or alkoxy;
  • “Lower alkyl” herein means, unless indicated otherwise, straight or branched alkyl having from 1 to 6 carbons and cycloalkyl having from 3 to 6 carbons.
  • C,-C 6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and structural isomers thereof.
  • R3 substituents are preferably hydrogen, methyl, difluoromethyl, dichloromethyl, hydroxymethyl, or methoxy and, most preferably, methyl.
  • the most preferred absolute configuration at C-5 of the oxazolidinone ring of the compounds according to the present invention is (S) under the Cahn-Ingold-Prelog nomenclature system. It is the (S)-enantiomer which possesses excellent activities against bacteria.
  • the racemic mixture can be used in the same way and for the same purpose as the pure (S)-enantiomer. However, the difference is that twice as much reacemic material must be used to exhibit the same antibacterial activity as the pure (S)-enantiomer.
  • the pharmaceutically acceptable salts of the compounds I include inorganic cation salts such as alkaline metal salts (e.g., sodium or potassium) and alkaline earth metal salts (e.g., calcium or magnesium), inorganic salts such as hydrochloride, hydrobromide, hydroiodide and sulfate, organic salts such as malate, lactate and tartarate, organic sulfonate such as benzenesulfonate, methanesulfonate and 4-tolunesulfonate, amino acid salts such as arginine, lysine and glycine, and amine salts such as trimethylamine, ammonia, triethylamine, pyridine, and picoline.
  • inorganic cation salts such as alkaline metal salts (e.g., sodium or potassium) and alkaline earth metal salts (e.g., calcium or magnesium), inorganic salts such as hydrochloride, hydrobromide, hydroi
  • the compounds I or pharmaceutically acceptable salts thereof of the present invention can be produced by reacting the above compounds II with the compounds of the formula III:
  • Xa is the same as X defined above, except for amine and protected amine, R 4 is hydrogen or carboxylic acid-protecting group, and L is halogen atom or acetoxy.
  • the halogen atom is chlorine, bromine or iodine. Bromine or idodine is especially preferable.
  • the compounds I of the present invention can be produced by acylating the compounds of the formula V:
  • Xb is amine or protected amine
  • R 5 is hydrogen or carboxylic acid-protecting group
  • M " is anionic halogen such as chloride, bromide or iodide, or sulfonate, acetate, benzenesulfonate or citrate anions, with the compounds of the formula VI:
  • M " is chloride or bromide.
  • the inner salt formed by monovalent anion of carboxylate and monovalent cation of pyridine is also preferable.
  • the compounds V can be prepared by C-3 reacting the compounds II with the compounds of the formula IV:
  • Xb is amine or protected amine
  • R 4 is hydrogen or carboxylic acid-protecting group
  • L is the same as defined above.
  • the reaction of the compounds II and the compounds III can be carried out at the temperature of from -30°C to 70°C.
  • the preferred solvent is anhydrous solvent.
  • the suitable organic solvents include lower nitrile such as acetonitrile and propionitrile, halogenated alkane such as chloroform, tetrachloromethane and dichloromethane, ether such as tetrahydrofuran and dioxane, amide such as N,N-dimethylformamide and N,N- dimethylacetamide, ester such as ethylacetate and methylacetate, ketone such as acetone, methylethylketone and methylisobutylketone, sulfoxide such as dimethylsulfoxide, aromatic hydrocarbon such as bezene and toluene, and mixtures thereof.
  • Protecting groups which do not participate in the displacement reaction of the compounds II and III may be introduced to amine, carboxyl and alcohol groups of the compounds II and III.
  • Examples of the amine-protecting group include formyl, acetyl, chloroacetyl, dichloroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, triphenyl, benzyl, 4- methoxybenzyl, diphenylmethyl, triloweralkylsilyl and trimethylsilyl.
  • the carboxyl- protecting groups include for example t-butyl, benzyl, 4-methoxybenzyl, benzyl, 4- nitrobenzyl, diphenylmethyl, methyl, 2,2,2-trichloroethyl, pivaloyloxymethyl, triloweralkylsilyl and trimethylsilyl.
  • Examples of the alcohol-protecting group include acetoxy, methoxymethyl, tetrahydrofuranyl, t-butyl, benzyl, and 4-methoxybenzyl.
  • amine, carboxyl and alcohol groups of the compounds II and III can be simultaneously protected by silylation.
  • silylating reagents can be used as a silylating reagent.
  • the silylating reagents are advantageous in that they make it possible to simultaneously protect amine, carboxyl and alcohol groups in an anhydrous solvent such as dichloromethane .
  • the compounds V can be obtained by reacting the compounds II with a silylating reagent such as N,O-bis(tri-loweralkylsilyl)acetamide or N,O-bis(tri-loweralkylsilyl) trifluoroacetamide in an anhydrous solvent such as dichloromethane or acetone at the temperature of from -30° to 60°C, followed by, if necessary, deprotecting, and crystalizing into hydrochloride, hydroiodide or sulfate salts or chromatographing over silical gel, alumina, resin, and the like.
  • a silylating reagent such as N,O-bis(tri-loweralkylsilyl)acetamide or N,O-bis(tri-loweralkylsilyl) trifluoroacetamide in an anhydrous solvent such as dichloromethane or acetone at the temperature of from -30° to 60°C, followed by, if necessary, deprotecting, and crystal
  • the compounds V can be obtained by simultaneously protecting amine and carboxyl groups with a silylating reagent such asN,O-bis(tri-loweralkylsilyl)acetamide,N,O-bis(tri-loweralkylsilyl)trifluoroacetamide or hexamethylsilazane(HMDS) and then converting acetoxymethyl into iodomethyl using iodotrimethylsilane.
  • a silylating reagent such asN,O-bis(tri-loweralkylsilyl)acetamide,N,O-bis(tri-loweralkylsilyl)trifluoroacetamide or hexamethylsilazane(HMDS)
  • the protection and deprotection of the functional groups can be conducted by a conventional method in the art, for example, "Protective groups in Organic Synthesis, 2nd edition” (Greene, T.W., etc., John Wiley & Sons, New York, 1991).
  • the pharmaceutically acceptable salts of the compounds II and III are the same as mentioned in the compounds I.
  • the compounds I of the present invention can be isolated and purified by conventional extraction, crystallization and column chromatography in the art.
  • the antibacterial composition containing the compounds I or pharmaceutically acceptable salts thereof as an active ingredient can be formulated into solid or liquid using conventional techniques in the art.
  • the pharmaceutical composition of the present invention can be primarily adminstered by intravenous or intramuscular injections.
  • the composition of the present invention can be used in the forms of capsule, tablet, powder, suppository, and the like.
  • Examples of the solid form containing the compounds I include powder, tablet, capsule, suppository, cachet, and the like.
  • the solid form can contain at least one of thickener, flavourant, sweetener, solubilizer, lubricant, suspending agent, binder, encapsulating agent, and the like.
  • Examples of nonactive solid carrier include magnesium carbonate, magnesium stearate, talc, glucose, lactose, pectin, dextrin, starch, gelatin, wax, coccoa butter, and the like.
  • the liquid formulation can be solution, suspension or emulsion.
  • Examples of the carrier for the liquid form include water, mixture of water and propyleneglycol, mixture of water and polypropyleneglycol, and the like. Additionally, additives such as pigment, solubilizer, sweetener, stabilizer, thickener, and the like can be included in the liquid formulation.
  • the antibacterial composition of the present invention can be applied directly to human and animals. In addition, it can be used as food preservatives, agricultural chemicals, and the like. When the composition of the present invention is used in the treatment of human or animals against microbial infection, the injection or oral administration is preferable.
  • the adminstration amount of the compounds I depends on sexuality, age, weight and symptom of the patients to be treated, administration route, and the like. Generally, the daily dosage is in the range of 1 mg/kg and 1 ,000 mg/kg. The preferable daily dosage is between 100 mg/kg and 500 mg/kg.
  • the compounds I of the present invention have broad activity against Gram- positive bacteria such as Streptococcus, Staphylococcus, Conellebacterium, Baccilus, Enterococci, and the like, and Gram-negative bacteria such as Escherichia coli, Klebsiella, Serratia marcescens, Salmonella, Proteus, and the like.
  • Gram- positive bacteria such as Streptococcus, Staphylococcus, Conellebacterium, Baccilus, Enterococci, and the like
  • Gram-negative bacteria such as Escherichia coli, Klebsiella, Serratia marcescens, Salmonella, Proteus, and the like.
  • the compounds I are effective against strains which are resistant to known antibiotics such as vancomycin, ⁇ -lactam antibiotics, quinolones, and the like.
  • the compounds I of the present invention are greatly valuable in that they can be used as an injection because their water solubility is at least 10%.
  • the known compounds indicated in the above Table 1 are active in vitro against Gram- positive bacteria and drug-resistant strains but their free bases cannot be used as an injection because of low solubility.
  • silylated pyridine derivative was prepared as follows. (S)-N-[[3-[3-fluoro-4-(4-pyridyl)phenyl]-2-oxo-5-oxazolidiny ⁇ ]- methyl] acetamide was used as a pyridine derivative and was synthesized according to the method described in international patent publication No. WO 93/09103. 5.65 g of the prydine derivative was mixed with 30 ml of acetonitrile.
  • the resulting oily residue was dissolved in 10 ml of anhydrous ethanol.
  • the resulting solution was mixed with an aqueous solution of 0.4 g of sodium hydroxide in 0.2 ml of distilled water and the mixture was stirred for 3 hours.
  • 10 ml of ethylacetate and 10 ml of water were added to the solution, and the solution was then stirred for 30 minutes. After the layers were separated, the organic layer was removed.2N HC1 was added to the aqueous layer to adjust its pH to 1.0.
  • This acylating reagent was dropwise added to the solution for 10 minutes and the solution was then stirred for 1 hour. After the reaction was completed, the solvent was removed and the residue was mixed with 50 ml of ethyl acetate. The resulting solid was filtered and suspended in 10 ml of dichloromethane. The suspension was reacted with 1.0 ml of trifluoracetic acid and 0.5 ml of anisol at 25°C for 1 hour. 20 ml of isopropyl ether was added to the reaction mixture and the resulting solid was filtered. After the unpurified solid was dissolved in an aqueous 50% ethanol, the pH of the solution was adjusted to 1.5 with 4N sulfuric acid and the resulting solution was concentrated under reduced pressure.
  • silylated pyridine derivative was prepared as follows.
  • Example 12 10 ml of anhydrous dichloromethane under nitrogen. After the same procedure as the Example 12 was carried out by using 1.3 ml of MSTFA and 0.5 ml of TMSI, the reaction mixture was concentrated under reduced pressure. The concentrate was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran for 5 minutes.
  • This silylated pyridine derivative was prepared as follows. (S)-N-[[3-[3-fluoro-4- (3-pyridyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (WO 93/09103).400 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25°C for 2 hours to produce the silylated pyridine derivative. The formed solid by adding 1.0 ml of methanol and 5 ml of acetonitrile to the solution was filtered, and purified to obtain 130 mg of the title compound. mp: 183 ° C to 186°C (decomposition)
  • This silylated pyridine derivative was prepared as follows. (S)-N-[[3-[4-(4- pyridyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (USP 5,254,577).380 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25 °C for 2 hours to produce the silylated pyridine derivative. The silylated pyridine derivative was added and the solution was stirred at 25°C for 3 hours. The formed solid was filtered by adding 1.0 ml of methanol and 5 ml of acetonitrile to the solution, and purified to obtain 150 mg of the title compound, mp: 196°C to 198°C (decomposition)
  • This silylated pyridine derivate was prepared as follows. (S)-N-[[3-[3,5-difluoro-4-(4-pyridyl)phenyl]- 2-oxo-5-oxazolidinyl]-methyl]acetamide was used as a pyridine derivative and was synthesized according to the known method (WO 93/09103). 420 mg of the pyridine derivative was added to 10 ml of acetonitrile and the resulting solution was reacted with 1.0 ml of MSTFA at 25 °C for 2 hours to produce the silylated pyridine derivative.
  • the solution was cooled to 5°C and was reacted with 0.5 ml of TMSI at 20°C for 30 minutes.
  • the solution was concentrated under reduced pressure and the residue was reacted with 10 ml of acetonitrile and 1 ml of tetrahydrofuran at 5°C for 5 minutes.
  • the solution was reacted at 25 °C for 3 hours with the silylated pyridine derivatives obtained by reacting 400 mg of (S)-N-[[3-[3-fluoro-4-(4-pyridyl)phenyl]-2-oxo-5-oxazolydinyl]- methyl] acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile.
  • the formed solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetonirile to the solution was filtered.
  • the solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate.
  • the solution was reacted at 25°C for 3 hours with the silylated pyridine derivatives obtained by reacting 400 mg of (S)-N-[[3-[3-fluoro-4- (3-pyridyl)phenyl]-2-oxo-5-oxazolydinyl]-methyl]acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile.
  • the resulting solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetoniril to the solution was filtered.
  • the solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate.
  • the solution was reacted at 25°C for 3 hours with the silylated pyridine derivatives obtained by reacting 380 mg of (S)-N-[[3-[4-(4- pyridyl)phenyl]-2-oxo-5-oxazolydinyl]-methyl]acetamide with 1.0 ml of MSTFA in 10 ml of acetonitrile.
  • the resulting solid by adding a mixed solvent of 1.0 ml of methanol and 5 ml of acetonirile to the solution was filtered.
  • the solid was dissolved in an aqueous 30% ethanol and the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate.
  • MRSA C5100 MetalUin resistant Staphylococcus aureus
  • C CRSA C6043 (Ciprofloxacin resistant Staphylococcus aureus)
  • D Staphylococcus epidermis ATCC 12228
  • E Enterococcus faecalis ATCC29212
  • F Streptococcus pyogenes ATCC8668
  • G Escherichia coli ATCC10536
  • the compounds of the formula I according to the present invention are broadly active against Gram-positive and Gram-negative bacteria and have the pharmacological advantages of vancomycin and cefotaxime. Especially, the compounds of the formula I are advantageous in that they are effective against cephem antibiotics-registant bacteria such as MRSA and CRSA.
  • the single dose toxicity of the compounds of the present invention was evaluated in ICR mice by intravenous administration.
  • the compounds of Examples 1 , 2 and 13 along with an equivalent of sodium bicarbonate were dissolved in saline and the resulting solutions were intravenously administered.
  • LD 50 of each test compound was measured to be 1,500 mg/kg of weight.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés du céphème, dans lesquels des dérivés connus de la phényloxazolidinone sont chimiquement combinés au céphème; un procédé permettant de produire des dérivés du céphème; et une composition pharmaceutique antibactérienne contenant lesdits dérivés. La formule structurelle de ces composés dérivés du céphème est représentée par la formule (I).
PCT/KR1998/000463 1997-12-26 1998-12-24 Composes derives du cepheme, procede de production associe et composition antibacterienne les contenant WO1999033839A1 (fr)

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Application Number Priority Date Filing Date Title
AU16940/99A AU1694099A (en) 1997-12-26 1998-12-24 Cephem derivatives and a method for producing the compounds and an antibacterialcomposition containing the compounds

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Application Number Priority Date Filing Date Title
KR19970073893 1997-12-26
KR1997/73893 1997-12-26
KR1019980050525A KR100294871B1 (ko) 1997-12-26 1998-11-20 세펨유도체화합물및이의제조방법및그를함유한항균제조성물
KR1998/50525 1998-11-20

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056819A1 (fr) * 2002-12-19 2004-07-08 Astrazeneca Ab Derives d'oxazolidinone utilises comme agents antibacteriens
WO2005061468A1 (fr) * 2003-12-17 2005-07-07 Rib-X Pharmaceuticals, Inc. Composes heterocycliques de biaryle halogenes et methodes de fabrication et d'utilisation
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
WO2006104141A1 (fr) * 2005-03-29 2006-10-05 Shionogi & Co., Ltd. Dérivé de 3-propénylcéphème
US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
US7148219B2 (en) 2003-06-03 2006-12-12 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7335753B2 (en) 2002-09-26 2008-02-26 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
US8883773B2 (en) 2010-04-05 2014-11-11 Shionogi & Co., Ltd. Cephem compound having pseudo-catechol group
US9145425B2 (en) 2010-04-05 2015-09-29 Shionogi & Co., Ltd. Cephem compound having catechol group
US9238657B2 (en) 2008-10-31 2016-01-19 Shionogi & Co., Ltd. Cephalosporin having catechol group
CN116535386A (zh) * 2023-04-19 2023-08-04 西南大学 氰乙烯磺酰苯胺类化合物及其制备方法和医药应用
US12115154B2 (en) 2020-12-16 2024-10-15 Srx Cardio, Llc Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009103A1 (fr) * 1991-11-01 1993-05-13 The Upjohn Company Aryl- et heteroarylphenyloxazolidinones substituees, utilisees comme agents antibacteriens
US5254577A (en) * 1988-07-29 1993-10-19 The Du Pont Merck Pharmaceutical Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254577A (en) * 1988-07-29 1993-10-19 The Du Pont Merck Pharmaceutical Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
WO1993009103A1 (fr) * 1991-11-01 1993-05-13 The Upjohn Company Aryl- et heteroarylphenyloxazolidinones substituees, utilisees comme agents antibacteriens

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7335753B2 (en) 2002-09-26 2008-02-26 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
WO2004056819A1 (fr) * 2002-12-19 2004-07-08 Astrazeneca Ab Derives d'oxazolidinone utilises comme agents antibacteriens
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US8895741B2 (en) 2003-06-03 2014-11-25 Melinta Therapeutics, Inc. Process for the synthesis of biaryl oxazolidinones
US7456206B2 (en) 2003-06-03 2008-11-25 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7705026B2 (en) 2003-06-03 2010-04-27 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US9550783B2 (en) 2003-06-03 2017-01-24 Melinta Therapeutics, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7148219B2 (en) 2003-06-03 2006-12-12 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7129259B2 (en) 2003-12-17 2006-10-31 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
WO2005061468A1 (fr) * 2003-12-17 2005-07-07 Rib-X Pharmaceuticals, Inc. Composes heterocycliques de biaryle halogenes et methodes de fabrication et d'utilisation
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8841263B2 (en) 2004-02-27 2014-09-23 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same
WO2006104141A1 (fr) * 2005-03-29 2006-10-05 Shionogi & Co., Ltd. Dérivé de 3-propénylcéphème
US8796465B2 (en) 2005-06-08 2014-08-05 Melinta Therapeutics, Inc. Process for the syntheses of triazoles
US9376400B2 (en) 2005-06-08 2016-06-28 Melinta Therapeutics, Inc. Process for the synthesis of triazoles
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
US9238657B2 (en) 2008-10-31 2016-01-19 Shionogi & Co., Ltd. Cephalosporin having catechol group
US8883773B2 (en) 2010-04-05 2014-11-11 Shionogi & Co., Ltd. Cephem compound having pseudo-catechol group
US9145425B2 (en) 2010-04-05 2015-09-29 Shionogi & Co., Ltd. Cephem compound having catechol group
US12115154B2 (en) 2020-12-16 2024-10-15 Srx Cardio, Llc Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9)
CN116535386A (zh) * 2023-04-19 2023-08-04 西南大学 氰乙烯磺酰苯胺类化合物及其制备方法和医药应用

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