WO2009034546A2 - Dérivés de trans-décahydroisoquinoline - Google Patents

Dérivés de trans-décahydroisoquinoline Download PDF

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Publication number
WO2009034546A2
WO2009034546A2 PCT/IB2008/053688 IB2008053688W WO2009034546A2 WO 2009034546 A2 WO2009034546 A2 WO 2009034546A2 IB 2008053688 W IB2008053688 W IB 2008053688W WO 2009034546 A2 WO2009034546 A2 WO 2009034546A2
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formula
methoxy
compound
octahydro
naphthyridin
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PCT/IB2008/053688
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English (en)
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WO2009034546A3 (fr
Inventor
Christian Hubschwerlen
Georg Rueedi
Jean-Philippe Surivet
Cornelia Zumbrunn Acklin
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Actelion Pharmaceuticals Ltd
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Publication of WO2009034546A3 publication Critical patent/WO2009034546A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention concerns novel trans-decahydroisoquinoline derivatives, a pharmaceutical antibacterial composition containing them and the use of these compounds in the manufacture of a medicament for the treatment of infections (e.g. bacterial infections).
  • infections e.g. bacterial infections
  • 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.
  • Enterobacteriacea 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.
  • WO 2004/087145 describes antibacterial compounds of the formula (Al)
  • Al wherein Zi can notably be N or CH, R 1 can notably be alkoxy, R 2 can be hydrogen or also, when Zi is not N, halogen, Wi can notably be N, W 4 can notably be CH, W 2 , W 3 , W5 and W 6 can notably each be a substituted methylene group, A-B can notably be a substituted ethylene group, R 10 can notably be hydrogen and R 11 can notably be a group -U-R 12 wherein U can notably be CH 2 or CO and R 12 is a substituted or unsubstituted bicyclic carbocyclic or heterocyclic ring system wherein at least one of the rings is aromatic.
  • B and W 3 or W 5 forming an additional ring is not mentioned.
  • WO 2006/081289 describes antibacterial compounds of the formula (A2)
  • WO 2006/081182 describes spiro annelated antibacterial compounds of the formula (A3)
  • A3 wherein Zi can notably be CH or N, Ri can notably be alkoxy, Z 2 and Z 5 can each notably be CH, Z 3 and Z 4 can each independently be N or CR la , R la can notably be hydrogen, halogen, hydroxy, alkyl, alkoxy, acyl or acyloxy, Wi, W 2 , W 3 , W 4 , W 5 , W 6 and W 7 are each CR 2 R 3 whereby R 2 and R 3 can notably each independently be hydrogen, hydroxy, alkyl, alkoxycarbonyl, amino, alkylamino or dialkylamino, A can notably be a bond, R 7 can notably be hydrogen and Rg is U-Rg wherein U can notably be CH 2 or CO and Rg is a substituted or unsubstituted bicyclic carbocyclic or heterocyclic ring system wherein at least one of the rings is aromatic.
  • WO 2004/096982 describes antibacterial compounds of the formula (A4)
  • R 1 can notably be alkoxy, one of Zi, Z 2 , Z 3 , Z 4 and Z 5 is N, one is or CR la and the remainder are CH
  • R la can notably be hydrogen, halogen, hydroxy, alkyl, alkoxy, acyl or acyloxy
  • A can notably represent a possibly substituted 5 membered aromatic heterocyclic ring
  • y is 1 or 2
  • R 2 can notably be hydrogen and R 3 can notably be a group -U-R 4 wherein U can notably be CH 2 or CO and R 4 is a substituted or unsubstituted bicyclic carbocyclic or heterocyclic ring system wherein at least one of the rings is aromatic.
  • WO 2006/105289 describes antibacterial compounds of the formula (A5)
  • R 1 can notably be hydrogen
  • R 2 can notably be unsubstituted or substituted aryl or heteroaryl
  • L 4 can notably be a bond and R 4 can notably be unsubstituted or substituted aryl or heteroaryl.
  • R 1 is alkoxy; one or two of U, V, W, X represent(s) N, the remaining represents CH, whereby V may also represent CR a , W may also represent CR b and X may also represent CR C ; R a is hydroxyalkyl;
  • R b is alkoxycarbonyl, carboxy or hydroxyalkyl;
  • R c is halogen;
  • R 2 is alkoxycarbonyl, carboxy, hydroxyalkyl or aminoalkyl;
  • B is the group:
  • Z is N or CH and the ring P is selected from the following:
  • D is aryl (especially 1 ,4-difluoro-2 -phenyl); and to salts (in particular pharmaceutically acceptable salts) of compounds of formula I.
  • the compounds of formula I may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond may be present in the Z- or ⁇ -configuration unless indicated otherwise.
  • the compounds of Formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • alkyl refers to a straight or branched chain alkyl group, containing from one to four carbon atoms.
  • Representative examples of alkyl groups include methyl, ethyl, propyl, ⁇ o-propyl, n-butyl, ⁇ o-butyl, sec-butyl and tert-butyl.
  • (Ci-C x )alkyl (x being an integer) refers to a straight or branched chain alkyl group containing 1 to x carbon atoms.
  • alkoxy refers to a straight or branched chain alkoxy group, containing from one to four carbon atoms. Representative examples of alkoxy groups include methoxy, ethoxy, propoxy, ⁇ o-propoxy, n-butoxy, ⁇ o-butoxy, sec-butoxy and tert-butoxy.
  • (Ci-C x )alkoxy refers to a straight or branched chain alkoxy group containing 1 to x carbon atoms.
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably to fluorine or chlorine.
  • hydroxyalkyl refers to a straight or branched chain alkyl group substituted once by hydroxy and containing from one to four carbon atoms. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl and 2- hydroxyethyl.
  • (Ci-C x )hydroxyalkyl (x being an integer) refers to a straight or branched chain hydroxyalkyl group containing 1 to x carbon atoms.
  • aminoalkyl refers to a straight or branched chain alkyl group substituted once by amino and containing from one to four carbon atoms. Representative examples of aminoalkyl include, but are not limited to, aminomethyl and 2-aminoethyl.
  • (Ci-C x )aminoalkyl (x being an integer) refers to a straight or branched chain aminoalkyl group containing 1 to x carbon atoms.
  • alkoxycarbonyl refers to an ester group wherein the alkoxy group is a straight or branched chain alkoxy group containing from one to four carbon atoms. Representative examples of alkoxycarbonyl include, but are not limited to, methoxy carbonyl and ethoxy carbonyl.
  • aryl refers to a phenyl group, which may be substituted one to three times by substituents each independently selected from the group consisting of halogen, alkyl, alkoxy and nitro.
  • substituents each independently selected from the group consisting of halogen, alkyl, alkoxy and nitro.
  • Representative examples of aryl include, but are not limited to, phenyl, 3-fluoro-phenyl and l,4-difluoro-2-phenyl.
  • the sign "*" placed near an atom will be used to designate the point of attachment of a radical to the rest of a molecule. For example:
  • room temperature refers to a temperature of 25°C.
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 0 C to Y plus 10 0 C, and preferably to an interval extending from Y minus 5 0 C to Y plus 5 0 C.
  • the invention relates to compounds of formula I that are also compounds of formula I C E wherein R 1 is alkoxy;
  • U and W each represent N
  • V represents CH or CR a , R a being hydroxyalkyl
  • X represents CH
  • V represents CH and X represents CR C
  • R c being halogen
  • W and X each represent N and U and V each represent CH, or U represents N, V and X each represent CH and W represents CR b , R b being alkoxycarbonyl;
  • R 2 is alkoxycarbonyl, carboxy, hydroxyalkyl or aminoalkyl
  • D is phenyl substituted by two halogen atoms (especially l,4-difluoro-2-phenyl); and to salts (in particular pharmaceutically acceptable salts) of compounds of formula I CE -
  • the compounds of formula I as defined in embodiment i) or ii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R 1 is (Ci-C3)alkoxy (notably methoxy or ethoxy and in particular methoxy).
  • Another preferred embodiment of this invention relates to the compounds of formula I as defined in embodiment i), ii) or iii) above or their salts (among which the pharmaceutically acceptable salts will be preferred) wherein U and W each represent N, V represents CH or CR a , R a being hydroxyalkyl, and X represents CH, or U and W each represent N, V represents CH and X represents CR C , R c being halogen (especially fluorine), or W and X each represent N and U and V each represent CH, U represents N, V and X each represent CH and W represents CR b , R b being alkoxycarbonyl.
  • the compounds of formula I or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that U and W each represent N and V and X each represent CH or CR C , R c being halogen (especially fluorine).
  • the compounds of formula I or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that U and W each represent N and V and X each represent CH.
  • the compounds of formula I or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that U and W each represent N, V represents CH and X represents CR C , R c being halogen (especially fluorine).
  • the compounds of formula I or their salts will be such that U and W each represent N, X represents CH and V represents CR a , R a being hydroxyalkyl (preferably (Ci -C 3 )IIy droxyalkyl and notably hydroxymethyl).
  • the compounds of formula I or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that W and X each represent N and U and V each represent CH.
  • the compounds of formula I or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that U represents N, V and X each represent CH and W represents CR b , R b being alkoxycarbonyl.
  • Yet another preferred embodiment of this invention relates to the compounds of formula I as defined in one of embodiments i) to ix) above or their salts (among which the pharmaceutically acceptable salts will be preferred) wherein R 2 is carboxy, hydroxyalkyl or aminoalkyl (and notably carboxy, hydroxymethyl or aminomethyl).
  • the compounds of formula I or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R 2 is carboxy.
  • the compounds of formula I or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that R 2 is hydroxyalkyl (notably (Ci -C 2 )IIy droxyalkyl and in particular hydroxymethyl).
  • the compounds of formula I or their salts will be such that R 2 is aminoalkyl (notably (Ci-C 2 )aminoalkyl and in particular aminomethyl).
  • B being selected from the group consisting of 3-oxo-3,4-dihydro- 2H-pyrido[3,2- ⁇ ][l,4]thiazine-6-yl and 3-
  • the compounds of formula I or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that A is CH 2 B, B being selected from the group consisting of 3-oxo-3,4-dihydro- 2H-pyrido[3,2- ⁇ ][l,4]thiazine-6-yl and 3-oxo-3,4-dihydro-2H-pyrido[3,2- ⁇ ][l,4]oxazine- 6-yl (B being in particular 3-oxo-3,4-dihydro-2H-pyrido[3,2- ⁇ ][l,4]thiazine-6-yl).
  • the compounds of formula I as defined in one of embodiments i) to xix) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that their decahydroisoquinoline ring has one of the configurations DHc or DH x :
  • the compounds of formula I as defined in embodiment xx) above or their salts (among which the pharmaceutically acceptable salts will be preferred) will be such that their decahydroisoquinoline ring has the configuration DHc.
  • the radical B when present in the compounds of formula I according to embodiment i) or any preferred embodiment, variant or subvariant according to embodiment i), will preferably be selected from the group consisting of 3-oxo-3,4-dihydro-2H-benzo[l,4]oxazine-6-yl, 3-oxo-3,4-dihydro-2H-benzo[l,4]thiazine- 6-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2- ⁇ ][l,4]thiazine-6-yl and 3-oxo-3,4-dihydro- 2H-pyrido[3,2- ⁇ ][l,4]oxazine-6-yl (B being notably 3-oxo-3,4-dihydro- 2H-pyrido[3,2- ⁇ ][l,4]thiazine-6-yl or 3-oxo-3,4-dihydro
  • Compounds of formula I are suitable for the use as chemotherapeutic active compounds in human and veterinary medicine and as substances for preserving inorganic and organic materials in particular all types of organic materials for example polymers, lubricants, paints, fibres, leather, paper and wood.
  • These 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, Enterococcus faecalis, E.faecium, E. casseliflavus, S. epidermidis, S.
  • haemolyticus or Peptostreptococcus spp.
  • pharyngitis rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum
  • respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae
  • blood and tissue infections including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E. faecalis, E.
  • faecium E. durans, including 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, Clostridium 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 Clostridium 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, Corynebacterium 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, Corynebacterium 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.
  • One aspect of this invention therefore relates to the use of a compound of fomula I according to this invention, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a bacterial infection.
  • bacterial infections can also be treated using compounds of formula I (or pharmaceutically acceptable salts thereof) in other species like pigs, ruminants, horses, dogs, cats and poultry.
  • the present invention also relates to pharmacologically acceptable salts and to compositions and formulations of compounds of formula I.
  • compositions according to the present invention contains at least one compound of formula I (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics.
  • the compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula I or 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.
  • Another aspect of the invention concerns a method for the prevention or the treatment of a bacterial infection in a patient comprising the administration to said patient of a pharmaceutically active amount of a derivative according to formula I or a pharmaceutically acceptable salt thereof.
  • any preferences indicated for the compounds of formula I (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formula I CE -
  • 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 reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent- water azeotrope or presence of drying agents such as molecular sieves, MgSO 4 or Na 2 SO 4 ).
  • solvent is typically toluene, Hex, THF, DCM or 1,2-DCE or mixture of solvents such as 1,2-DCE/MeOH.
  • the reaction can be catalyzed by traces of acid (usually AcOH).
  • the intermediate imine is reduced with a suitable reducing agent (e.g. NaBH 4 , NaBHCN 3 , or NaBH(OAc) 3 or through hydrogenation over a noble catalyst such as Pd/C.
  • a suitable reducing agent e.g. NaBH 4 , NaBHCN 3 , or NaBH(OAc) 3 or through hydrogenation over a noble catalyst such as Pd/C.
  • the reaction is carried out between -10 0 C and 110 0 C, preferably between 0 0 C and 60 0 C.
  • the reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in presence of a picoline-borane complex ⁇ Tetrahedron (2004), 60, 7899-7906).
  • the carboxylic acid is reacted with the amine in presence of an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or di-(JV-succinimidyl)- carbonate, in a dry aprotic solvent such as DCM, MeCN or DMF between -2O 0 C and +6O 0 C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 6, p. 381).
  • an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or di-(JV-succinimidyl)- carbonate
  • the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between -20° and +60 0 C. Further activating agents can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2 nd Edition, R. C. Larock, Wiley- VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999. Section nitriles, carboxylic acids and derivatives p.1941-1949.
  • THF THF is treated between -20 0 C and 70 0 C with either an aluminium hydride reagent such as LiAlH 4 or NaAlH 2 (OCH 2 CH 2 OMe) 2 or a borohydride reagent such as NaBH 4 .
  • an aluminium hydride reagent such as LiAlH 4 or NaAlH 2 (OCH 2 CH 2 OMe) 2
  • a borohydride reagent such as NaBH 4 .
  • P . a . rt_4_ . hydrolysis ; . of an . ester ;into_ an , acid;
  • the hydrolysis is usually performed by treatment with an alkali hydroxide such as LiOH, KOH or NaOH in a water-dioxane or water -THF mixture between 0 0 C and 80 0 C.
  • an alkali hydroxide such as LiOH, KOH or NaOH
  • the hydrolysis can also be performed in neat TFA or diluted TFA or HCl in an organic solvent such as ether or THF.
  • the reaction is performed in presence of tetrakis(triphenylphosphine)palladium(0) in presence of an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0 0 C and 50 0 C in a solvent such as THF.
  • an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0 0 C and 50 0 C in a solvent such as THF.
  • the ester side chain is benzyl
  • the reaction is performed under hydrogen in presence of a noble metal catalyst such as Pd/C in a solvent such as MeOH, THF or EA.
  • Part . 5 conversion of an . alcohol . into . an amine . : .
  • the alcohol is reacted with MsCl, TfCl or TsCl in presence of a base such as TEA in a dry aprotic solvent such as Pyr, THF or DCM between -30 0 C and 50 0 C.
  • a base such as TEA
  • a dry aprotic solvent such as Pyr, THF or DCM between -30 0 C and 50 0 C.
  • Tf 2 O or Ms 2 O can also be used.
  • the resulting sulfonate is reacted with sodium azide in a solvent such as THF or DMF between 20 0 C and 100 0 C.
  • the resulting azide is converted into the corresponding amine after either hydrogenolysis over a noble metal catalyst such as Pd/C or platinum in a solvent such as THF, methanol or ethyl acetate, or by reaction with PPh 3 followed by the addition of water.
  • a noble metal catalyst such as Pd/C or platinum in a solvent such as THF, methanol or ethyl acetate, or by reaction with PPh 3 followed by the addition of water.
  • the sulfonate or the halogenide is reacted with the corresponding amine in presence of an organic base such as DIPEA in a solvent such as DMF between 50 0 C and 110 0 C.
  • Amines are usually protected as carbamates such as Alloc, Cbz, Fmoc or Boc. They are obtained by reacting the amine with allyl, fluorenylmethyl or benzyl chloroformate or with di tert-butyl dicarbonate in presence of a base such as NaOH, TEA, DMAP or imidazole. Further strategies to introduce other amine protecting groups have been described in Protecting Groups in Organic Synthesis, 3rd Ed (1999), 494-653; T.W. Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N. Y.).
  • the benzyl carbamates are deprotected by hydrogenolysis over a noble catalyst (e.g. Pd/C or Pd(OH) 2 ZC).
  • a noble catalyst e.g. Pd/C or Pd(OH) 2 ZC.
  • the Boc group is removed under acidic conditions such as HCl in an organic solvent such as MeOH or dioxane, or TFA neat or diluted in a solvent such DCM.
  • Further general methods to remove amine protecting groups have been described in Protecting Groups in Organic Synthesis, 3 rd Ed (1999), 494-653; T.W. Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y.).
  • the alcohol derivative is treated with the desired silylchloride (e.g. TMSCl, TBDMSCl) in a solvent such as THF or DCM between -20 0 C and 50 0 C in presence of an organic base such as TEA and traces of DMAP or imidazole.
  • TMSCl silylchloride
  • TBDMSCl a solvent
  • an organic base such as TEA and traces of DMAP or imidazole.
  • the silyl ether groups are removed either using fluoride anion sources such as TBAF in THF between 0 0 C and 40 0 C or HF in MeCN between 0 0 C and 40 0 C or using acidic conditions such as AcOH in THF/MeOH or HCl in MeOH. Further methods to remove the TBDMS, TMS and TBDPS groups are given in Protecting Groups in Organic Synthesis 3 rd Ed; 1999, 133-139 and 142-143 respectively; T.W.Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y.).
  • the alcohol or phenol is treated in a solvent such as THF, DCM or DMF between -20 0 C and 60 0 C with N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethylsulfonyl anhydride or trifluoromethylsulfonyl chloride in presence of an organic base such as TEA or DIPEA.
  • a solvent such as THF, DCM or DMF between -20 0 C and 60 0 C
  • N-phenyl-bis(trifluoromethanesulfonimide) trifluoromethylsulfonyl anhydride or trifluoromethylsulfonyl chloride
  • an organic base such as TEA or DIPEA.
  • the compounds of formula I can be manufactured in accordance with the present invention by a) reaction of a compound of formula II
  • R 1 , R 2 , U, V, W, X are as in formula I with an aldehyde of formula III
  • R 1 , U, V, W, X are as in formula I and R 2 represents alkoxycarbonyl or hydroxyalkyl with an amine of formula VIII
  • the compounds of formula I thus obtained may, if desired, be converted into their salts, and notably into their pharmaceutically acceptable salts.
  • the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 mm) column, a Daicel ChiralCel OD-H (5-10 mm) column, or a Daicel ChiralPak IA (10 mm) or AD-H (5 mm) column.
  • a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 mm) column, a Daicel ChiralCel OD-H (5-10 mm) column, or a Daicel ChiralPak IA (10 mm) or AD-H (5 mm) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
  • the compounds of formula II can be obtained by deprotection of compounds of formula IX as described in part 7 of the section "General reaction techniques".
  • the compounds of formula II can also be obtained as summarised in Scheme 1 hereafter.
  • R 1 , R 2 , U, V, W, X are as in formula I, L 1 represents halogen or OTf and PG 1 represents an amine protecting group such as Boc, Fmoc or Cbz.
  • the compounds of formula II can thus be obtained (Scheme 1) from the intermediate of formula V after reaction with the amine of formula X, as described in part 6 of the section "General reaction techniques” followed by sequential reductive amination of the ketone of formula VII with benzylamine as described in part 1 of the section “General reaction techniques” followed by hydrogenolysis over a noble metal catalyst such as Pd/C or platinum oxide.
  • the compounds of formula IX can be obtained by reaction of the intermediate of formula V with the amine of formula XI as described in part 6 of the section "General reaction techniques".
  • R represents alkyl and PG 1 represents an amine protecting group such as Cbz or Fmoc.
  • the compounds of formula XVI can be transformed into the compounds of formula VI after reductive amination with the aldehydes of formula III followed by removal of the Boc protecting group as described in part 7 of the section "General reaction techniques".
  • the amines of formula XVI can also be protected as Cbz or Fmoc derivatives of formula XIII as described in part 8 of the section "General reaction techniques".
  • the Boc group of these ⁇ -protected amines can then be removed as described in part 7 of the section "General reaction techniques” to afford the compounds of formula XV, which can be further elaborated into the compounds of formula XI wherein R 2 is hydroxymethyl or aminomethyl following procedures described in parts 3 and 5 of the section "General reaction techniques”.
  • the compounds of formula XIII can be further elaborated into the compounds of formula XIV wherein R 2 is hydroxymethyl or aminomethyl as described in part 3 and 5 of the section "General reaction techniques".
  • PG 2 represents TMS or TBDMS.
  • the compound of formula V can then be obtained by converting the resulting naphthyridinol derivative of formula XIX into the corresponding triflate (see part 11 of the section "General reaction techniques") and removing the silyl protecting group PG 2 (see part 10 of the section “General reaction techniques”).
  • R' is H, OH or OMe and AIk is alkyl.
  • vinyl boronic acids such as tr ⁇ ns-2-phenylvinyl boronic acid
  • a palladium catalyst such as Pd[P(Ph) 3 J 4
  • a diazomethane derivative such as TMSCHN 2 .
  • the benzyl ether protecting group of the compounds of formula XXIV can then be removed upon hydrogenolysis over a noble metal catalyst such as Pd/C and the intermediate obtained further transformed into the corresponding triflate of formula V as described in part 11 of the section "General reaction techniques".
  • the compounds of formula VIII are obtained from the corresponding aldehydes of formula III after reduction into the corresponding alcohol and transformation into the corresponding amine as described in part 5 of the section "General reaction techniques".
  • Example 1 (4aS,6R,8aR)-6- [(£)-3-(2,5-difluoro-phenyl)-allylamino] -2-(6-methoxy- [l,5]naphthyridin-4-yl)-octahydro-isoquinoline-8a-carboxylic acid methyl ester and ( ⁇ flR,6S,SflS)-6-[( ⁇ )-3-(2,5-difluoro-phenyl)-allylamino]-2-(6-methoxy- [l,5]naphthyridin-4-yl)-octahydro-isoquinoline-8a-carboxylic acid methyl ester:
  • Example 2 (4aS,6S,8aR)-6-[(E)-3-(2,5-dinuoro-phen ⁇ )-s ⁇ s ⁇ mmo]-2-(6-metho ⁇ - [l,5]naphthyridin-4-yl)-octahydro-isoquinoline-8a-carboxylic acid methyl ester and (4aR,6RM ⁇ -H( ⁇ - ⁇ - ⁇ oro-pheny ⁇ )-a ⁇ y ⁇ ammo]-2-(6-methoxy-
  • Example 3 (4flS,6S,SflR)-2-(6-methoxy-[l,5]naphthyridin-4-yl)-6-[(3-oxo- 3,4-dihydro-2H-pyrido[3,2-6] [l,4]thiazin-6-ylmethyl)-amino]-octahydro-isoquinoline- 8a-carboxylic acid methyl ester and (4 ⁇ R,6R,S ⁇ S)-2-(6-methoxy-[l,5]naphthyridin- 4-yl)-6- [(3-oxo-3,4-dihydro-2H-pyrido [3,2-6] [1,4] thiazin-6-ylmethyl)-amino] - octahydro-isoquinoline- ⁇ a-carboxylic acid methyl ester:
  • reaction mixture was filtered over hydromatrix ® (treated with sat. NaHCOs) and the filtrate was evaporated under reduced pressure. The residue was purified over SiO 2
  • Example 4 ( ⁇ flS,6S,SflR)-2-(6-methoxy-[l,5]naphthyridin-4-yl)-6-[(3-oxo- 3,4-dihydro-2H-pyrido[3,2-6] [l,4]thiazin-6-ylmethyl)-amino]-octahydro-isoquinoline- 8a-carboxylic acid and ( ⁇ R,6R,SflS)-2-(6-methoxy-[l,5]naphthyridin-4-yl)-6-[(3-oxo- 3,4-dihydro-2H-pyrido[3,2-6] [l,4]thiazin-6-ylmethyl)-amino]-octahydro-isoquinoline- 8a-carboxylic acid:
  • Example 5 ( ⁇ S,6S,SflR)-6-[(£)-3-(2,5-difluoro-phenyl)-allylamino]-2-(6-methoxy- [l,5]naphthyridin-4-yl)-octahydro-isoquinoline-8a-carboxylic acid and (4flR,6R,SflS)-6-[(£)-3-(2,5-difluoro-phenyl)-allylamino]-2-(6-methoxy- [l,5]naphthyridin-4-yl)-octahydro-isoquinoline-8a-carboxylic acid:
  • Example 4 Starting from a mixture of the compound mixtures of Example 2 and Example 1 (5:1, 0.055 g, 0.105 mmol), the title compounds were obtained as a white solid (0.024 g, 45% yield) using the procedure of Example 4.
  • the crude product was purified by chromatography over SiO 2 (DCM-MeOH 93-7 containing 1% aq. NH 4 OH), followed by trituration in ether.
  • Example 7 (4aS,6SMR)-H(fy-3 ⁇ 2,5-Mftuoro-vheny ⁇ )-a ⁇ y ⁇ ammo]-2-(6-methoxy- quinazolin-4-yl)-octahydro-isoquinoline-8a-carboxylic acid methyl ester and (4flR,6R,SflS)-6-[(£)-3-(2,5-difluoro-phenyl)-allylamino]-2-(6-methoxy-quinazolin- 4-yl)-octahydro-isoquinoline-8a-carboxylic acid methyl ester:
  • Example 8 [(4aS,6S,8aR)-H(E)-3-(2,5-dinuoro-pheny ⁇ )-a ⁇ ly ⁇ ammo]-2-(6-methoxy- quinazolin-4-yl)-octahydro-isoquinolin-8a-yl] -methanol and [(4flR,6R,SflS)-6-[(£)-3-(2,5-difluoro-phenyl)-allylamino]-2-(6-methoxy-quinazolin- 4-yl)-octahydro-isoquinolin-8a-yl]-methanol:
  • Example 7 Starting from the mixture of compounds of Example 7 (0.095 g, 0.18 mmol), the title compounds were obtained as a yellowish foam (0.014 g, 16% yield) using the procedure of Example 6, step 6.iv.
  • the crude material was purified by column chromatography over SiO 2 (DCM-MeOH 97-3 containing 0.3% aq. NH 4 OH then DCM-MeOH 19-1 containing 0.5% aq. NH 4 OH).
  • Example 11 (4aS,6S,8aR)- [8a-aminomethyl-2-(6-methoxy- [ 1 ,5] naphthyridin-4-yl)- decahydro-isoquinolin-6-yl]-[(£)-3-(2,5-difluoro-phenyl)-allyl]-amine:
  • Example 12 2-(( ⁇ S,6S,SflR)-8- ⁇ 6-[( ⁇ )-3-(2,5-difluoro-phenyl)-allylamino]- 8a-hydroxymethyl-octahydro-isoquinolin-2-yl ⁇ -2-methoxy-[l,5]naphthyridin-4-yl)- ethanol and 2-(( ⁇ R,6R,SflS)-8- ⁇ 6-[( ⁇ )-3-(2,5-difluoro-phenyl)-allylamino]- 8a-hydroxymethyl-octahydro-isoquinolin-2-yl ⁇ -2-methoxy-[l,5]naphthyridin-4-yl)- ethanol:
  • Example 13 6-( ⁇ ( ⁇ S,6S,SflR)-2-[8-(2-hydroxy-ethyl)-6-methoxy-[l,5]naphthyridin- 4-yl]-8a-hydroxymethyl-decahydro-isoquinolin-6-ylamino ⁇ -methyl)-
  • Example 15 6- ⁇ [( ⁇ flS,6S,S «R)-2-(3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)- 8a-hydroxymethyl-decahydro-isoquinolin-6-ylamino]-methyl ⁇ - 4H-pyrido [3,2-6] [l,4]thiazin-3-one and 6- ⁇ [( ⁇ R,6R,S ⁇ S)-2-(3-fluoro-6-methoxy- [l,5]naphthyridin-4-yl)-8a-hydroxymethyl-decahydro-isoquinolin-6-ylamino]- methyl ⁇ -4H-pyrido [3,2-6] [l,4]thiazin-3-one:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des composés antibactériens de formule (I) dans laquelle R1 représente un groupe alcoxy, un ou deux des éléments U, V, W, X représente(nt) N, les autres représentant CH, V pouvant également représenter CRa, W pouvant également représenter CRb et X pouvant également représenter CRc ; Ra représentant un groupe hydroxyalkyle ; Rb un groupe alcoxycarbonyle, carboxy or hydroxyalkyle ; Rc un halogène, R2 un groupe alcoxycarbonyle, carboxy, hydroxyalkyle ou aminoalkyle, A représentant CH2B, C(=O)B ou CH2CH=CHD, B représentant le groupe (II) dans lequel Z représente N ou CH et le noyau P est choisi parmi les composés de formule (III) dans laquelle Q représente O ou S, et D un groupe aryle (par exemple le 1,4-difluoro-2-phényle).
PCT/IB2008/053688 2007-09-13 2008-09-12 Dérivés de trans-décahydroisoquinoline WO2009034546A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015193506A1 (fr) * 2014-06-20 2015-12-23 Institut Pasteur Korea Composés anti-infectieux

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087145A2 (fr) * 2003-03-27 2004-10-14 Glaxo Group Limited Agents antibacteriens
WO2006081182A2 (fr) * 2005-01-25 2006-08-03 Glaxo Group Limited Agents antibacteriens
WO2006105289A1 (fr) * 2005-03-31 2006-10-05 Janssen Pharmaceutica N.V. Composes de pyrazole bicycliques utilises comme agents antibacteriens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087145A2 (fr) * 2003-03-27 2004-10-14 Glaxo Group Limited Agents antibacteriens
WO2006081182A2 (fr) * 2005-01-25 2006-08-03 Glaxo Group Limited Agents antibacteriens
WO2006105289A1 (fr) * 2005-03-31 2006-10-05 Janssen Pharmaceutica N.V. Composes de pyrazole bicycliques utilises comme agents antibacteriens

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015193506A1 (fr) * 2014-06-20 2015-12-23 Institut Pasteur Korea Composés anti-infectieux
CN107027307A (zh) * 2014-06-20 2017-08-08 韩国巴斯德研究所 一种抗感染化合物
RU2753403C2 (ru) * 2014-06-20 2021-08-16 Институт Пастер Корея Противоинфекционные соединения
US11279714B2 (en) 2014-06-20 2022-03-22 Institut Pasteur Korea Anti-infective compounds

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