WO2006099884A1 - Antibiotiques beta-aminoalcools - Google Patents

Antibiotiques beta-aminoalcools Download PDF

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Publication number
WO2006099884A1
WO2006099884A1 PCT/EP2005/003154 EP2005003154W WO2006099884A1 WO 2006099884 A1 WO2006099884 A1 WO 2006099884A1 EP 2005003154 W EP2005003154 W EP 2005003154W WO 2006099884 A1 WO2006099884 A1 WO 2006099884A1
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compound according
methoxy
piperidin
formula
quinolin
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PCT/EP2005/003154
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English (en)
Inventor
Christian Hubschwerlen
Jean-Philippe Surivet
Cornelia Zumbrunn Acklin
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Actelion Percurex Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention concerns novel antibiotics, pharmaceutical antibacterial composition containing them and use thereof in the manufacture of a medicament for the treatment of infections (e.g. bacterial infection).
  • infections e.g. bacterial infection
  • These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including among others Gram positive and Gram negative aerobic and anaerobic bacteria and mycobacteria.
  • Enterohacteriacea are cephalosporin and quinolone resistant;
  • - P. aeruginosa are ⁇ -lactam and quinolone resistant.
  • microorganisms that are causing persistent infections are increasingly being recognized as causative agents or cofactors of severe chronic diseases like peptic ulcers or heart diseases.
  • Certain l-piperidyl-2-(quinolin-4-yl)-ethanol derivatives have already been described in WO 02/08224, WO 02/056882, WO 03/064421 and WO 03/064431 as antibacterial agents.
  • quinolinyl aminoalcohols are useful antimicrobial agents and particularly effective against a variety of multi-drug resistant bacteria.
  • the present invention relates to the quinolinyl aminoalcohols of the formula I
  • R 1 represents alkyl, alkoxy, halogen or cyano
  • R 2 represents hydrogen or halogen
  • R 3 represents hydrogen or halogen
  • one of the symbols W 1 and W 2 represents CH and the other represents CH or N
  • U represents oxygen or sulphur
  • V represents CO or CH 2 .
  • a further embodiment of the novel quinolinyl aminoalcohols of the above formula I relates to their optically pure enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, meso forms, pharmaceutically acceptable acid addition salts, solvent complexes and morphological forms thereof.
  • Particularly preferred are the optically pure enantiomers, optically pure diastereoisomers, meso forms, pharmaceutically acceptable acid addition salts, solvent complexes and morphological forms.
  • Any reference to a compound of formula I is thus to be understood as referring also to configurational isomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts, solvent complexes, and morphological forms of such compounds, as appropriate and expedient.
  • the present invention also relates to pro-drugs of a compound of formula I that convert in vivo to the compound of formula I as such. Any reference to a compound of formula I is therefore to be understood as referring also to the corresponding prodrugs of the compound of formula I, as appropriate and expedient.
  • alkyl refers to a saturated straight or branched chain alkyl group, containing from one to six, in particular one to three carbon atoms, for example methyl, ethyl, propyl, zso-propyl, butyl, wo-butyl, sec-butyl, tert-butyl, n-pentyl, w ⁇ -pentyl, n-hexyl, 2,2-dimethylbutyl.
  • alkoxy refers to an "alkyl-O" group, wherein “alkyl” has the above significance (e.g. methoxy, ethoxy, propoxy, zso-propoxy, butoxy, w ⁇ -butoxy, sec-butoxy, tert-bntoxy, rc-pentoxy, neopentyloxy, wo-pentyloxy, n-hexyloxy or zso-hexyloxy).
  • An alkoxy group will preferably contain one to three carbon atoms.
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably to fluorine or chlorine.
  • Preferred quinolinyl aminoalcohols of formula I are compounds wherein R 1 represents C]-C 3 alkoxy, especially methoxy; or R 2 represents hydrogen; or R 3 represents hydrogen; or W represents CH or N and W represents CH; or V represents CH 2 and their pharmaceutically acceptable acid addition salts.
  • quinolinyl aminoalcohols of formula I are those wherein each of R 1 , R 2 , R 3 , W 1 , W 2 and V has the preferred significance indicated above.
  • the quinolinyl aminoalcohols of formula I will be such that U is oxygen. According to another preferred embodiment of the instant invention, the quinolinyl aminoalcohols of formula I will be such that U is sulphur.
  • Especially preferred compounds of formula I are the following: • 6-( ⁇ (2R)- 1 -[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-piperidin-4-ylamino ⁇ - methyl)-4i/-benzo[ 1 ,4]oxazin-3-one;
  • Compounds of formula I are suitable for the use as chemotherapeutic active compounds in human and veterinary medicine.
  • the compounds according to the invention are particularly active against bacteria and bacteria-like organisms. They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens as well as disorders related to bacterial infections comprising pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enter ococcus faecalis, E. faecium, E. casselflavus, S.
  • strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., S. epidermidis, S.
  • Streptococcus pyogenes Streptococcus agalactiae, Streptococcal groups C-F (minute colony streptococci), viridans streptococci, Corynebacterium minutissimum, Closfridium spp., or Bartonella henselae
  • uncomplicated acute urinary tract infections related to infection by Staphylococcus aureus, coagulase-negative staphylococcal species, or Enterococcus spp.
  • urethritis and cervicitis sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae
  • aureus food poisoning and toxic shock syndrome
  • Groups A, B, and C streptococci ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H.
  • MAC Mycobacterium avium complex
  • chelonei gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Closfridium perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease related to infection by Helicobacter pylori or Chlamydia pneumoniae.
  • Compounds of formula I according to the present invention are further useful for the preparation of a medicament for the treatment of infections that are mediated by bacteria such as E. coli, Klebsiella pneumoniae and other enterobacteriaceae, Acinetobacter spp., Stenothrophomonas maltophilia, Neisseria meningitidis, Bacillus cereus, Bacillus anthracis, Cot ⁇ nebacterium spp., Propionibacterium acnes and bacteroide spp.
  • bacteria such as E. coli, Klebsiella pneumoniae and other enterobacteriaceae, Acinetobacter spp., Stenothrophomonas maltophilia, Neisseria meningitidis, Bacillus cereus, Bacillus anthracis, Cot ⁇ nebacterium spp., Propionibacterium acnes and bacteroide spp.
  • Compounds of formula I according to the present invention are further useful to treat protozoal infections caused by Plasmodium malaria, Plasmodium falciparum, Toxoplasma gondii, Pneumocystis carinii, Trypanosoma brucei and Leishmania spp.
  • bacterial infections can also be treated in other species like pigs, ruminants, horses, dogs, cats and poultry.
  • the present invention also relates to pharmaceutically acceptable salts, or solvates and hydrates, respectively, and to compositions and formulations of compounds of formula I.
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphorous acid, nitrous acid, citric acid, formic acid, acetic acid, oxalic acid, maleic acid, lactic acid, tartaric acid, fumaric acid, benzoic acid, mandelic acid, cinnamic acid, pamoic acid, stearic acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanedisulfonic acid, p-toluenesulfonic acid, salicylic acid, succinic acid, trifluoroacetic acid, and the like that are non toxic to living organisms or, in case the compound of formula (I) is acidic in nature, with an inorganic base like an alkali or earth alkali base, e.g. sodium hydrox
  • Compounds of formula I may be solvated, especially hydrated.
  • the hydration can occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula I.
  • the pharmaceutical composition according to the present invention contains at least one compound of formula I as the active agent and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics.
  • compounds of formula I can be administered, for example, perorally, e.g. as tablets, coated tablets, dragees, soft and hard gelatine capsules, pills, aqueous or oily solutions, emulsions, suspensions or syrups, rectally, e.g. in the form of suppositories, parenterally e.g. in the form of injection or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
  • perorally e.g. as tablets, coated tablets, dragees, soft and hard gelatine capsules, pills, aqueous or oily solutions, emulsions, suspensions or syrups, rectally, e.g. in the form of suppositories, parenterally e.g. in the form of injection or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
  • Another aspect of the invention concerns a method for the treatment of an infectious disease comprising the administration to the patient in need thereof of a therapeutically effective amount of a compound of formula I.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of formula I and their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the compounds of formula I may also be used for cleaning purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments or to make a room or an area aseptic.
  • the compounds of formula I could be contained in a solution or in a spray formulation.
  • the compounds of formula I can be manufactured in accordance with the present invention by
  • PG is a nitrogen protecting group, such as benzyloxycarbonyl, allyloxycarbonyl or t-butyloxycarbonyl, and R 1 , R 2 and R 3 are as above, and treating the N-deprotected product with a compound of formula V
  • R is chloromethyl, bromomethyl, methanesulfonyloxymethyl, trifluoromethanesulfonyloxymethyl, toluenesulfonyloxymethyl, formyl or an activated form of a carboxylic acid and W 1 , W 2 and U are as above, or
  • the reaction between the compounds of formulas II and III is preferably carried out in the presence of a Lewis acid such as lithium perchlorate in the presence of an alkali metal carbonate, such as potassium carbonate, in an organic solvent such as DMF at a temperature ranging between 2O 0 C and 100 0 C, more preferably at a temperature in the vicinity of 80°C.
  • a Lewis acid such as lithium perchlorate
  • an alkali metal carbonate such as potassium carbonate
  • organic solvent such as DMF
  • protecting groups are suitable, such as a t-butoxycarbonyl group (Boc), allyloxycarbonyl group (Alloc) or a benzyloxycarbonyl group (Cbz).
  • Boc t-butoxycarbonyl group
  • Alloc allyloxycarbonyl group
  • Cbz benzyloxycarbonyl group
  • a variety of other protecting groups may be used as reviewed in Protecting groups, Kocienski, PJ. , Thieme (1994).
  • several strategies may be used to unmask the amino group, such as trifluoroacetic acid in the case of Boc and Cbz group or hydrogenolysis using a catalyst such as palladium of charcoal and hydrogen in the case of the Cbz group.
  • R 4 is chloromethyl, bromomethyl, methanesulfonyloxymethyl, trifluoromemanesulfonyloxymethyl, toluenesulfonyloxymethyl or formyl to yield a compound of formula I, where V is CH 2 ; or, wherein R 4 is an activated form of a carboxylic acid, to yield a compound of formula I, where V is CO.
  • R is formyl or carboxy.
  • the reaction is carried out with a compound of formula V wherein R 4 is formyl under reductive amination conditions as reviewed in R.O. and M.K.
  • HATU N, ⁇ f ⁇ /yV4etramethyluronium hexafluorophosphate
  • reaction between the compounds of formulas VII and VIII is preferably carried out in the following way.
  • Z is CO
  • the reaction is performed under reductive amination conditions as reviewed in R.O. and M.K. Hutchins Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 25-78.
  • the reaction is performed in the presence of an organic base such as triethylarnine or Hiinig base, in an organic solvent such as DMF, dichloromethane or THF at a temperature ranging between 0°C and 60°C, more preferably at a temperature in the vicinity of 3O 0 C.
  • an organic base such as triethylarnine or Hiinig base
  • an organic solvent such as DMF, dichloromethane or THF
  • the aldehydes X may be obtained by reaction of the bromide under carbon monoxide pressure in presence of a palladium catalyst.
  • the bromide may also be transformed to the aromatic nitrile using conditions reported in J. Org. Chem. (2005), 70, 1508-1510 and subsequent controlled reduction of the nitrile using diisobutylaluminum hydride in a solvent such as THF, dichloromethane at a temperature ranging between -8O 0 C and 20 0 C, most preferably at a temperature in the vicinity of 0 0 C.
  • Reagents and Conditions a. BrPPh 3 , BuLi, -78°C, THF. b. AD-mix ⁇ , fBuOH-H 2 O, O 0 C, 24h. c. pTsCI, Et 3 N, then K 2 CO 3 , MeOH. d. MeC(OEt)3, pTsOH, DCM, rt then TMSCI, DCM, rt, then K 2 CO 3 ,
  • the aldehydes X are transformed into the corresponding alkenes by treatment with the phosphorous ylide generated by deprotonation of triphenylphosphonium bromide using a base such as n-butyllithium in THF at a temperature ranging between -78°C and 1O 0 C.
  • the alkenes are transformed into the corresponding chiral diols XI using the Sharpless asymmetric dihydroxylation protocol as described in Chem. Rev. (1994), 94, 2483.
  • Both enantiomers of the diols XI are accessible, using either a chiral ligand based on dihydroquinine (contained in the commercially available AD mix ⁇ ) or based on dihydroquinidine (commercially contained in the commercially available AD mix ⁇ ).
  • a chiral ligand based on dihydroquinine obtained in the commercially available AD mix ⁇
  • dihydroquinidine commercially contained in the commercially available AD mix ⁇
  • the primary alcohol is selectively transformed into a leaving group, such as methanesulfonyloxy or /?ara-toluenesulfonyloxy, by treatment with methanesulfonyl chloride or para- toluenesulfonyl chloride in the presence of an organic base such as triethylamine or pyridine at a temperature ranging between — 78°C and O 0 C, more preferably at a temperature ranging between -30°C and -10 0 C.
  • a leaving group such as methanesulfonyloxy or /?ara-toluenesulfonyloxy
  • the resulting methane- or toluene- sulfonyloxy derivatives are transformed into the desired epoxides II by treatment with an inorganic base such as potassium carbonate in a solvent such as methanol or ethanol.
  • the diols are transformed into the corresponding epoxides II using the methodology developed by Sharpless and reported in Tetrahedron (1992), 48, 10515.
  • Compounds of formula III are obtained by deprotecting compounds of formula XII.
  • protecting groups (PG) are suitable in this process such as a t-butoxycarbonyl group (Boc), allyloxycarbonyl group (Alloc) or a benzyloxycarbonyl group (Cbz).
  • Compounds of formula XII are obtained by reacting an iV-protected 4-aminopiperidine XIII with a compound of formula V wherein R 4 is chloromethyl, bromomethyl, methanesulfonyloxymethyl, trifluoromethanesulfonyloxymethyl, toluenesulfonyloxymethyl or formyl to yield a compound of formula XII, where V is CH 2 ; or, wherein R 4 is an activated form of a carboxylic acid, to yield a compound of formula XII, where V is CO.
  • R 4 is formyl or carboxy.
  • a 4-amino-piperidine-l -carboxylic acid ester of formula XIII is reacted with a compound of formula V wherein R 4 is formyl under reductive amination conditions as reviewed in R.O. and M.K. Hutchins Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p.
  • R 4 is COOH
  • an activating agent such as l-(dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDC) or 1 -hydroxybenzotriazole (HOBT) or (9-(7-azabenzotriazol- 1 -yl)-N, ⁇ N',N'-tetramethyluronium hexafluorophosphate
  • Compounds of formula IV are obtained by reacting a compound of formula II with a N-protected-4-amino piperidine XIV.
  • the reaction is promoted by a Lewis acid such as lithium perchlorate in a solvent such as DMF at a temperature ranging between 20°C and 100°C, more preferably at a temperature in the vicinity of 80 0 C.
  • a Lewis acid such as lithium perchlorate
  • a solvent such as DMF
  • protecting groups PG
  • protecting groups such as a ter£-butoxycarbonyl group (Boc), allyloxycarbonyl group (Alloc) or a benzyloxycarbonyl group (Cbz).
  • Reagents and Conditions a. LiCIO 4 , K 2 CO 3 , DMF, 80°C b. TFA, rt c. H 2 , 10% Pd-C, AcOEt
  • protecting groups may be used as reviewed in Protecting groups, Kocienski, P. J. Thieme (1994). According to the nature of the protecting group, several strategies may be used to unmask the amino group, such as trifluoroacetic acid in the case of Boc and Cbz group or hydro genolysis using a catalyst such as palladium of charcoal and hydrogen in the case of the Cbz group.
  • Compounds of formula V wherein R 4 is formyl are prepared according to WO 02/056882 and WO 03/087098.
  • Compounds V wherein R 4 is CH 2 OH or COOH are respectively obtained by reduction of the aldehyde using sodium borohydride in alcoholic solvent or by oxidation of the aldehyde using either silver nitrate in acetonitrile, sodium hypochlorite in a buffered medium or chromium oxide as an oxidizing agent.
  • the CH 2 OH group R 4 is further transformed into a leaving group, such as methanesulfonyloxy or p ⁇ ra-toluenesulfonyloxy, by treatment with methanesulfonyl chloride or para-toluene sulfonyl chloride in the presence of an organic base such as triethylamine or pyridine at a temperature ranging between -78°C and O 0 C, more preferably at a temperature ranging between -3O 0 C and -10 0 C in an organic solvent such as THF, DMF or dichloromethane.
  • a leaving group such as methanesulfonyloxy or p ⁇ ra-toluenesulfonyloxy
  • the resulting methane- or toluene-sulfonyloxy derivatives are transformed into the corresponding bromides or iodides by treatment with sodium bromide or iodide respectively, in presence of an inorganic base such as potassium carbonate in a solvent such as acetone, THF or DMF.
  • R 5 is a leaving group, preferably chlorine or bromine.
  • the reaction is expediently carried out in the presence of an organic base such as triethylamine or H ⁇ nig base or an alkali metal carbonate, such as potassium carbonate, in an organic solvent such as DMF at a temperature ranging between 20 0 C and 100 0 C, more preferably at a temperature in the vicinity of 60 0 C.
  • N-protected-4-amino piperidines XIII and XIV are either commercially available or may be prepared as described in literature.
  • 6-carbaldehyde prepared according to WO 03/064421, 0.065 g, 0.36 mmol.
  • the reaction mixture was heated at 50°C overnight. After cooling to rt, sodium borohydride (0.1 g) was added and the reaction proceeded for two hours.
  • the reaction mixture was filtered through ⁇ ydromatrix , previously treated with sodium bicarbonate (6 ml). The filtrate was concentrated to dryness.
  • the filtrate was purified over silica gel (DCM-MeOH 19-1 with 1% aq. ammonium hydroxide) to afford the title compound (0.081 g, 0.17 mmol) as a white foam.
  • Example 3 6-( ⁇ (2R)-l-[2-hydroxy-2-(3-methoxy-quinolin-5-yl)-ethyl]-piperidin- 4-ylamino ⁇ -methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one: Starting from (2i?)-2-(4-amino-piperidin-l-yl)-l-(3-methoxy-quinolin-5-yl)-ethanol (0.1 g, 0.33 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-£][l,4]thiazine- 6-carbaldehyde (prepared according to WO 03/064421, 0.068 g, 0.35 mmol), and using the procedure described in Example 1 (step l.xi), the title product (0.073 g, 0.15 mmol) was obtained as a white foam after purification over silica gel using DCM-MeOH 19-1 containing
  • Example 6 6-(c/s- ⁇ 3-fluoro-l-[(2 ⁇ )-2-hydroxy-2-(3-methoxy-quinolin-5-yl)- ethyl]-piperidin-4-ylamino ⁇ -methyl)-4H-pyrido[3,2-b][l,4]thiazin-3-one
  • F.fa E. faecalis
  • E. fm E faecium
  • S p S. pneumoniae
  • H infl H influenzae
  • M cat M catharralis
  • P. Aer P. aeruginosa.
  • the quinolinyl aminoalcohols of formula I present a better antibacterial activity, especially against resistant strains.

Abstract

Cette invention concerne des composés actifs sur le plan antimicrobien de formule (I) dans laquelle R1 représente un groupe alkyle, un groupe alcoxy, un halogène ou un groupe cyano; R2 représente l’hydrogène ou un halogène; R3 représente l’hydrogène ou un halogène; l’un des symboles W1 et W2 représente un groupe CH et l’autre représente un groupe CH ou N; U représente l’oxygène ou le soufre ; et V représente un groupe CO ou un groupe CH2; de même que leurs énantiomères optiquement purs, leurs mélanges d’énantiomères, leurs racémates, leurs diastéréoisomères optiquement purs, leurs mélanges de diastéréoisomères, leurs racémates diastéréoisomères, leurs mélanges de racémates diastéréoisomères, leurs formes méso, leurs sels d’addition d’acide pharmaceutiquement acceptables, leurs complexes de solvants et leurs formes morphologiques.
PCT/EP2005/003154 2005-03-24 2005-03-24 Antibiotiques beta-aminoalcools WO2006099884A1 (fr)

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EP2005995A1 (fr) * 2007-06-22 2008-12-24 Glaxo Group Limited Composés hétérocycliques pour le traitement de la tuberculose
EP2080761A1 (fr) 2008-01-18 2009-07-22 Glaxo Group Limited Composés
WO2010043714A1 (fr) 2008-10-17 2010-04-22 Glaxo Group Limited Composés azotés tricycliques utilisés comme agents antibactériens
WO2010081874A1 (fr) 2009-01-15 2010-07-22 Glaxo Group Limited Composés naphthyridine-2(1h)-one utiles comme antibactériens
WO2010084152A1 (fr) 2009-01-21 2010-07-29 Basilea Pharmaceutica Ag Nouveaux antibiotiques bicycliques
US7875715B2 (en) 2005-06-16 2011-01-25 Astrazeneca Ab Compounds for the treatment of multi-drug resistant bacterial infections
US8389524B2 (en) 2007-04-20 2013-03-05 Glaxo Group Limited Tricyclic nitrogen containing compounds as antibacterial agents
WO2016027249A1 (fr) 2014-08-22 2016-02-25 Glaxosmithkline Intellectual Property Development Limited Composés contenant de l'azote tricyclique pour le traitement de l'infection à neisseria gonorrhoeae
WO2019011200A1 (fr) * 2017-07-10 2019-01-17 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé de pyridine carboxamide et son intermédiaire
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
US10836771B2 (en) 2017-03-20 2020-11-17 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
US11980611B2 (en) 2022-12-22 2024-05-14 Novo Nordisk Health Care Ag Treating sickle cell disease with a pyruvate kinase R activating compound

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US8389524B2 (en) 2007-04-20 2013-03-05 Glaxo Group Limited Tricyclic nitrogen containing compounds as antibacterial agents
EP2005995A1 (fr) * 2007-06-22 2008-12-24 Glaxo Group Limited Composés hétérocycliques pour le traitement de la tuberculose
WO2009000745A1 (fr) * 2007-06-22 2008-12-31 Glaxo Group Limited Composés hétérocycliques pour le traitement de la tuberculose
CN101778651A (zh) * 2007-06-22 2010-07-14 葛兰素集团有限公司 用于治疗结核病的杂环化合物
EP2080761A1 (fr) 2008-01-18 2009-07-22 Glaxo Group Limited Composés
WO2010043714A1 (fr) 2008-10-17 2010-04-22 Glaxo Group Limited Composés azotés tricycliques utilisés comme agents antibactériens
WO2010081874A1 (fr) 2009-01-15 2010-07-22 Glaxo Group Limited Composés naphthyridine-2(1h)-one utiles comme antibactériens
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WO2010084152A1 (fr) 2009-01-21 2010-07-29 Basilea Pharmaceutica Ag Nouveaux antibiotiques bicycliques
US8716280B2 (en) 2009-01-21 2014-05-06 Basilea Pharmaceutica Ag Bicyclic antibiotics
EP3639824A1 (fr) 2014-08-22 2020-04-22 GlaxoSmithKline Intellectual Property Development Limited Composés tricyclique contenant de l'azote pour le traitement de l'infection à neisseria gonorrhoeae
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US11014927B2 (en) 2017-03-20 2021-05-25 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US11649242B2 (en) 2017-03-20 2023-05-16 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
CN109983008A (zh) * 2017-07-10 2019-07-05 江苏恒瑞医药股份有限公司 一种吡啶甲酰胺类衍生物的制备方法及其中间体
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US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
US11071725B2 (en) 2018-09-19 2021-07-27 Forma Therapeutics, Inc. Activating pyruvate kinase R
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US11980611B2 (en) 2022-12-22 2024-05-14 Novo Nordisk Health Care Ag Treating sickle cell disease with a pyruvate kinase R activating compound

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