[go: up one dir, main page]

WO2018193124A1 - Dérivés d'azithromycine contenant un ion phosphonium utilisés en tant qu'agents antibactériens - Google Patents

Dérivés d'azithromycine contenant un ion phosphonium utilisés en tant qu'agents antibactériens Download PDF

Info

Publication number
WO2018193124A1
WO2018193124A1 PCT/EP2018/060244 EP2018060244W WO2018193124A1 WO 2018193124 A1 WO2018193124 A1 WO 2018193124A1 EP 2018060244 W EP2018060244 W EP 2018060244W WO 2018193124 A1 WO2018193124 A1 WO 2018193124A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
independently
phenyl
occurrence
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2018/060244
Other languages
English (en)
Inventor
Tim SPAREY
Andrew Ratcliffe
Brett Stevenson
Franz LAGASSE
Edward COCHRANE
Alexandre Froidbise
David Hallett
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novintum Biotechnology GmbH
Original Assignee
Novintum Biotechnology GmbH
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
Application filed by Novintum Biotechnology GmbH filed Critical Novintum Biotechnology GmbH
Publication of WO2018193124A1 publication Critical patent/WO2018193124A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • This invention relates to ions and compounds comprising said ions that can be used to treat bacterial infections, and particularly infections caused by Gram-negative bacterial strains that are resistant to other antibiotics.
  • the ions are azithromycin derivatives having a phosphonium cation tethered to the azithromycin macrocycle.
  • the invention also relates to methods of using said ions and compounds and to pharmaceutical formulations comprising said ions and compounds.
  • Staphylococcus aureus e.g. Methicillin Resistant Staphylococcus Aureus (MRSA)
  • MRSA Methicillin Resistant Staphylococcus Aureus
  • S. Aureus is a Gram- positive bacteria and infections caused by Gram-positive bacteria can be treated effectively by a broader range of antibiotics than can be used to treat infections caused by Gram-negative bacteria.
  • Gram-negative bacteria have an outer membrane that Gram-positive bacteria lack and this outer membrane provides protection against a range of antibiotics.
  • a number of Gram-negative bacteria that were identified as high priority included clarithromycin-resistant Helicobacter pylori, fluoroquinolone-resistant Campylobacter, fluoroquinolone-resistant Salmonella spp., and 3 rd generation cephalosporin- resistant and fluoroquinolone-resistant Neisseria gonorrhoeae.
  • Azithromycin is a broad-spectrum antibiotic. It is widely used for treating bacterial infections caused by both Gram-negative and Gram-positive bacteria.
  • a compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 5 is independently selected from H, C(0)-Ci-C6-alkyl or R 5 has the structure:
  • R 1a , R 1 b and R 1c are each independently selected from: phenyl; biphenyl; naphthyl; 5-, 6-, 9- or 10- membered heteroaryl; C3 to Cs-cycloalkyl; Ci-Cs-alkyl and 4- to 8-membered heterocycloalkyl, wherein said phenyl, biphenyl, naphthyl, or 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 6 groups, and wherein said C3 to Cs-cycloalkyl, Ci-Ce-alkyI and 4- to 8-membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R 7 groups; wherein R 1a and R 1 b are optionally connected to each other via a bond or a group selected from -0-, N R 6a , and Ci- C3-alkylene;
  • R 2a , R 2b and R 6a are each independently selected from H and Ci-C6-alkyl;
  • R 3a is independently selected from H, Ci-C6-alkyl or C(0)-Ci-C6-alkyl;
  • R 3b and R 3c are each independently selected from: H or C(0)-Ci-C6-alkyl
  • R 4a and R 4b are each independently selected from: H or C(0)-Ci-C 6 -alkyl; or R 4a and R 4b taken together form C(O);
  • R 6 is independently at each occurrence selected from: Ci-C6-alkyl; C2-C6-alkynyl; C2-C6- alkenyl; Ci-C6-haloalkyl; C3-C6-cycloalkyl; 5- to 8-membered heterocycloalkyl; 5-, 6-, 9- or 10- membered heteroaryl; phenyl; OR 8 ; N R 9 R 11 ; SR 9 ; C(0)OR 9 ; C(0)N R 9 R 9 ; OC(0)N R 9 R 9 ; N R 9 C(0)OR 9 ; halo; cyano; nitro; C(0)R 9 ; S(0) 2 OR 9 ; S(0) 2 R 9 ; S(0)R 9 ; and S(0) 2 N R 9 R 9 ;
  • R 7 is independently at each occurrence selected from: oxo; Ci-C6-alkyl; C2-C6-alkynyl; C2-C6- alkenyl; Ci-C6-haloalkyl; C3-C6-cycloalkyl; 5- to 8-membered heterocycloalkyl; 5-, 6-, 9- or 10- membered heteroaryl; phenyl; OR 8 ; N R 9 R 11 ; SR 9 ; C(0)OR 9 ; C(0)N R 9 R 9 ; halo; cyano; nitro; C(0)R 9 ; S(0) 2 OR 9 ; S(0) 2 R 9 ; S(0)R 9 ; OC(0)N R 9 R 9 ; N R 9 C(0)OR 8 and S(0) 2 N R 9 R 9 ;
  • -L 1 - and -L 3 - are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R 13 groups; provided that any -L 1 - or -L 3 - group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4-alkylene-; -L 2 - is independently at each occurrence either absent or selected from: -0-, -S-, -NR 11 -, - C(0)-, -OC(O)-, -C(0)0-, -S(0) 2 -, -S(0)-, -NR 10 C(O)-, -C(0)NR 10 , -NR 10 S(O) 2 -, -S(0) 2 NR 10 -, - OC(O)NR 10 -,-NR 10 C(O)O-, NR 10 C(O)NR 10
  • R 8 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl;
  • R 9 and R 10 are each independently at each occurrence selected from: H and Ci-C6-alkyl;
  • R 11 is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0) 2 -Ci-C 6 -alkyl;
  • R 12 is independently at each occurrence selected from H, Ci-C4-alkyl and halo;
  • R 13 is independently at each occurrence selected from: Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6- alkenyl, Ci-C 6 -haloalkyl, OR 8 , NR 9 R 11 , SR 9 , C(0)OR 1 °, C(0)NR 9 R 9 , halo, cyano, nitro, C(0)R 9 , S(0) 2 OR 9 , S(0) 2 R 9 , S(0)R 9 and S(0) 2 NR 9 R 10 ; and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6-alkenyl, C1-C6- haloalkyl,
  • the invention also provides a compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 a , R 1 b and R 1 c are each independently selected from: phenyl; biphenyl; naphthyl; 5-, 6-, 9- or 10- membered heteroaryl; C3 to Cs-cycloalkyl; Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi, wherein said phenyl, biphenyl, naphthyl, or 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 6 groups, and wherein said C3 to Cs-cycloalkyl, d-Cs-alkyl and 5- to 8-membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R 7 groups;
  • R 2a and R 2b are each independently selected from H and Ci-C6-alkyl
  • R 3a is independently selected from H , Ci-C6-alkyl or C(0)-Ci-C6-alkyl;
  • R 3b and R 3c are each independently selected from: H or C(0)-Ci-C6-alkyl
  • R 4a and R 4b are each independently selected from: H or C(0)-Ci-C 6 -alkyl; or R 4a and R 4b taken together form C(O);
  • -L 1 - and -L 3 - are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R 13 groups; provided that any -L 1 - or -L 3 - group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4-alkylene-;
  • R 8 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl;
  • R 9 and R 10 are each independently at each occurrence selected from: H and Ci-C6-alkyl;
  • R 11 is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0) 2 -Ci-C 6 -alkyl;
  • R 12 is independently at each occurrence selected from H , Ci-C4-alkyl and halo;
  • R 13 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C 6 -haloalkyl, OR 8 , NR 9 R 10 , SR 9 , C(0)OR 1 °, C(0)NR 9 R 9 , halo, cyano, nitro, C(0)R 9 , S(0) 2 OR 9 , S(0) 2 R 9 , S(0)R 9 and S(0) 2 NR 9 R 1 °; and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6- haloalkyl, OR a , NR
  • each -L 2 -L 3 - unit is selected independently of the other each -L 2 -L 3 - unit or -L 2 -L 3 - units.
  • each -L 2 -L 3 - unit may be the same or they may be different.
  • the atom length of the linkers formed by L 1 , L 2 and L 3 is the number of atoms in a straight chain from the phosphorous atom of the phosphonium to the carbon atom via which the linker is attached to the azithromycin portion of the molecules.
  • the length does not include any substituents or branching that might be present on the chain.
  • the left-hand portion of the linker group is attached, either directly or indirectly, to the carbon atom via which the linker is attached to the azithromycin macrocyclic portion of the ion and the right hand portion of the linker group is attached, either directly or indirectly, to the phosphorous atom of the phosphonium.
  • the ion of formula (I) is an ion of formula (I I):
  • L 4 is a C3-Cis-alkylene group optionally substituted with from 0 to 10 R 13 groups.
  • R 5 is
  • R 5 is is H.
  • R 5 is
  • R 5 is R 3c is H.
  • R 2a is Ci-C 6 alkyl.
  • R 2a is methyl
  • R 2b is Ci-C 6 alkyl.
  • R 2b is methyl
  • R 2a is Ci-C 6 alkyl and R 2b is Ci-C 6 alkyl.
  • R 2a is methyl and R 2b is methyl.
  • R 3a is H.
  • R 3b is H.
  • R 3a is H and R 3b is H.
  • R 3c is H.
  • R 4a is H.
  • R 4b is H.
  • R 4a is H and R 4b is H.
  • R 5 is , R 2a i s Ci-C 6 alkyl
  • R 2b is Ci-C 6 alkyl
  • R : is H
  • R 3b is H
  • R 4a is H
  • R 4b is H.
  • R 5 is , R 3c i s H, R 2a is methyl, R 2b is methyl, R 3a is H, R 3b is H, R 4a is H and R 4b is H.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, 5- or 6- membered heteroaryl and C3 to Cs-cycloalkyl, wherein said phenyl, biphenyl and 5- or 6- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 6 groups, and wherein said C3 to Cs-cycloalkyl is optionally substituted with from 1 to 5 independently selected R 7 groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with from 1 to 5 independently selected R 6 groups, and wherein said cyclohexyl group is optionally substituted with from 1 to 5 independently selected R 7 groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 6 groups, and wherein said cyclohexyl group is optionally substituted with 1 to 3 independently selected R 7 groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 6 groups, provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, optionally substituted with from 1 to 5 independently selected R 6 groups, provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 independently selected R1 d groups, provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 R 6 groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from C3 to Cs cycloalkyi, Ci-Cs-alkyI and 4- to 8- membered heterocycloalkyi; wherein said C3 to Cs cycloalkyi, Ci-Cs-alkyI and 4- to 8- membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R 7 groups.
  • R 1a , R 1b and R 1c are each independently selected from C3 to Cs cycloalkyi, Ci-Cs-alkyl and 5- to 8- membered heterocycloalkyi; wherein said C3 to Cs cycloalkyi, Ci-Cs-alkyl and 5- to 8- membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R 7 groups.
  • R 1a , R 1b and R 1c are different or the same.
  • R 7 is independently at each occurrence selected from Ci-C6-alkyl, halo, OR 8 , NR 9 R 11 and S(0) 2 OR 9 .
  • R 7 is independently at each occurrence selected from OCH3, OCH 2 (CH 3 ) 2 , N(CH 3 ) 2 , S0 2 OH, F and CI.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 6 groups, wherein R 6 is independently at each occurrence selected from Ci-C 6 -alkyl, halo, OR 8 , NR 9 R 11 and S(0) 2 OR 9 .
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 6 groups, wherein R 6 is independently at each occurrence selected from OCH 3 , OCH 2 (CH 3 ) 2 , N(CH 3 ) 2 , S0 2 OH, F and CI.
  • R 1a is C 3 to Cs-cycloalkyl
  • R 1b is C 3 to Cs-cycloalkyl
  • R 1c is C 3 to Cs-cycloalkyl
  • R 1a and R 1b are each unsubstituted phenyl and R 1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C 3 to Cs-cycloalkyl, Ci-Cs-alkyl and 4- to 8-membered heterocycloalkyl.
  • R 1a and R 1b are each unsubstituted phenyl and R 1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl,
  • R 1a and R 1b are each unsubstituted phenyl and R 1c is substituted phenyl.
  • R 1a and R 1b are each unsubstituted phenyl and R 1c is pyridyl.
  • R 1a and R 1b are each C 3 to Cs-cycloalkyl and R 1c is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, Ci-Cs-alkyl and 4- to 8-membered heterocycloalkyl.
  • R 1a and R 1b are each C 3 to Cs-cycloalkyl and R 1c is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyl.
  • R 1a and R 1b are each cyclohexyl and R 1c is substituted biphenyl.
  • R 1a , R 1b and R 1c are each substituted phenyl. It may be that R 1a , R 1b and R 1c are each fluorophenyl, e.g. para-fluorophenyl. It may be that R 1a , R 1b and R 1c are each chlorophenyl, e.g. para-chlorophenyl. It may be that R 1a , R 1b and R 1c are each methoxyphenyl, e.g. para-methoxyphenyl. [0053] In embodiments, R 1a , R 1b and R1 c are each C3 to Cs-cycloalkyl. In embodiments, R 1a , R 1b and R 1c are each cyclohexyl.
  • R 1a , R 1b and R 1c are each benzyl.
  • R 1a , R 1b and R 1c are each unsubstituted phenyl.
  • R 1a and R 1b are connected to each other via a bond or a group selected from -0-, NR 6a , and Ci-C3-alkylene. It may be that R 1a and R 1b are connected to each other via a bond or a Ci-C3-alkylene group. It may be that R 1a and R 1b are connected to each other via a bond. It may be that R 1a and R 1b are each phenyl and are connected to each other via a bond or a group selected from -0-, NR 6a , and Ci-C3-alkylene.
  • R 1a and R 1b are each phenyl and are connected to each other via a bond or a Ci-C3-alkylene group. It may be that R 1a and R 1b are each phenyl and are connected to each other via a bond.
  • R 1a and R 1b are not connected to each other via a bond or a group selected from -0-, NR 6a , and Ci-C3-alkylene.
  • - + PR 1a R 1b R 1c is selected from - + P(Ph) 3 ,
  • L 2 is at each occurrence absent.
  • the group -L 1 -(L 2 - L 3 ) n - may form an alkylene linker group.
  • L 2 is at each occurrence -O- and -L 3 - is at each occurrence -C2-C4-alkylene-.
  • the group -(L 2 -L 3 ) n - may form a ether or polyether linker group.
  • -L 3 - may at each occurrence represent -CH2CH2- or-CH 2 CH 2 CH 2 -.
  • the group -(L 2 -L 3 ) n - may form a, ethylene glycol, polyethyleneglycol, propyleneglycol or polypropylene glycol linker group.
  • L 2 is at each occurrence -NR 10 C(O)-, -C(0)NR 10 .
  • the group— (L 2 -L 3 ) n - may form a peptide linker group.
  • -L 3 - is at each occurrence -Ci-alkylene-.
  • L 2 is -C(0)NR 10 .
  • L 2 is -C(0)NCH 3 -.
  • L 1 , L 2 , L 3 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.
  • L 1 -(L 2 -L 3 ) n - represents -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, - (CH 2 ) 8 -, -(CH 2 ) 9 - and -(CH 2 )io-.
  • L 1 -(L 2 -L 3 ) n - represents -(CH 2 ) 5 C(0)N(CH 3 )CH 2 CH 2 -
  • R 1a R 1b R 1c is:
  • L 5 is a C2-Cis-alkylene group optionally substituted with from 0 to 10 R 13 groups.
  • L 5 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R 13 groups.
  • L 5 may be unsubstituted.
  • L 5 may be a C6-alkylene group.
  • L 5 may be a Cs-alkylene group
  • R 1a R 1b R 1c is: ; wherein L 4 is a C3-C15- alkylene group optionally substituted with from 0 to 10 R 13 groups. L 4 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R 13 groups. L 4 may be unsubstituted.
  • the ion of formula (I) is selected from:
  • the ion of formula (I) will be associated with an anionic counter ion.
  • the ion of formula (I) will be associated with a pharmaceutically acceptable anionic counterion.
  • the first aspect of the invention also, therefore, provides a compound comprising the ion of formula (I) and a pharmaceutically acceptable anion.
  • the anion may have a single negative charge.
  • the anion may be selected from: halo (e.g.
  • each anion listed in the preceding sentence possesses a single negative charge.
  • the anion may have multiple negative charges, e.g. P0 4 3" or CO3 2" .
  • the anion may be derived from a di- or tri-acid, e.g.
  • carboxylate anions may each be accompanied by a pharmaceutically acceptable metal cation or by another ion of formula (I).
  • the anion is Br, CF 3 C(0)0, or HC(0)0.
  • the anion is selected from CI, Br, I, PF 6 , CF 3 C(0)0, or HC(0)0.
  • the anions associated with the cations of the invention can be quite labile. It may be therefore that the cation of the invention is present associated with two or more different anions. Ion exchange processes can be used to control the identity of the anion associated with the cation of the invention.
  • the compounds of the invention are for medical use.
  • the compounds of the present invention are for use in treating a bacterial or mycobacterial infection.
  • a method for the treatment of a bacterial or mycobacterial infection comprising the administration of a therapeutically effective amount of a compound of the present invention.
  • the bacterial infection may be a Gram-negative bacterial infection.
  • the bacterial or mycobacterial infection e.g. the Gram-negative bacterial infection, may be resistant to at least one antibiotic.
  • treatment may be taken to include prevention. Treatment also encompasses any improvement of pathology, symptoms or prognosis that is achieved in respect of an infection in a subject receiving a compound of the invention. Treatment may be indicated by a partial improvement of such indications (e.g., the reduction of infection following medical use of the compounds of the invention), or by a total improvement (e.g., the absence of infection following medical use of a compound of the invention).
  • composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may be a combination product comprising one or more different pharmaceutically active agents.
  • the one or more additional pharmaceutically active agents may be another antibiotic.
  • the one or more pharmaceutically active agents may include a compound that increases the effectiveness of an antibiotic, e.g. by sensitising the bacteria to the antibiotic.
  • the invention also comprises the following numbered clauses: 1 .
  • a compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 5 is independently selected from H, C(0)-Ci-C6-alkyl or R 5 has the structure:
  • R 1a , R 1b and R 1c are each independently selected from: phenyl; biphenyl; naphthyl; 5-, 6-, 9- or 10- membered heteroaryl; C3 to Cs-cycloalkyl; Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyl, wherein said phenyl, biphenyl, naphthyl, or 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 6 groups, and wherein said C3 to Cs-cycloalkyl, d-Cs-alkyl and 5- to 8-membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R 7 groups;
  • R 2a and R 2b are each independently selected from H and Ci-C6-alkyl
  • R 3a is independently selected from H, Ci-C6-alkyl or C(0)-Ci-C6-alkyl;
  • R 3b and R 3c are each independently selected from: H or C(0)-Ci-C6-alkyl
  • R 4a and R 4b are each independently selected from: H or C(0)-Ci-C 6 -alkyl; or R 4a and R 4b taken together form C(O);
  • R 6 is independently at each occurrence selected from: Ci-C6-alkyl; C2-C6-alkynyl; C2-C6- alkenyl; Ci-C6-haloalkyl; C3-C6-cycloalkyl; 5- to 8-membered heterocycloalkyl; 5-, 6-, 9- or 10- membered heteroaryl; phenyl; OR 8 ; NR 9 R 10 ; SR 9 ; C(0)OR 9 ; C(0)NR 9 R 9 ; OC(0)NR 9 R 9 ; NR 9 C(0)OR 9 ; halo; cyano; nitro; C(0)R 9 ; S(0) 2 OR 9 ; S(0) 2 R 9 ; S(0)R 9 ; and S(0) 2 NR 9 R 9 ;
  • R 7 is independently at each occurrence selected from: oxo; Ci-C6-alkyl; C2-C6-alkynyl; C2-C6- alkenyl; Ci-C6-haloalkyl; C3-C6-cycloalkyl; 5- to 8-membered heterocycloalkyl; 5-, 6-, 9- or 10- membered heteroaryl; phenyl; OR 8 ; NR 9 R 10 ; SR 9 ; C(0)OR 9 ; C(0)NR 9 R 9 ; halo; cyano; nitro; C(0)R 9 ; S(0) 2 OR 9 ; S(0) 2 R 9 ; S(0)R 9 ; OC(0)NR 9 R 9 ; NR 9 C(0)OR 8 and S(0) 2 NR 9 R 9 ;
  • -L 1 - and -L 3 - are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R 13 groups; provided that any -L 1 - or -L 3 - group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4-alkylene-;
  • R 8 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl;
  • R 9 and R 10 are each independently at each occurrence selected from: H and Ci-C6-alkyl;
  • R 11 is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0) 2 -Ci-C 6 -alkyl;
  • R 12 is independently at each occurrence selected from H , Ci-C4-alkyl and halo;
  • R 13 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C 6 -haloalkyl, OR 8 , NR 9 R 10 , SR 9 , C(0)OR 1 °, C(0)NR 9 R 9 , halo, cyano, nitro, C(0)R 9 , S(0) 2 OR 9 , S(0) 2 R 9 , S(0)R 9 and S(0) 2 NR 9 R 1 °; and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2-
  • R 1a , R 1b and R 1c are each C3 to Cs- cycloalkyl.
  • R 1a and R 1b are each unsubstituted phenyl and R 1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi.
  • R 1a and R 1b are each C3 to Cs- cycloalkyl and R 1c is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, d-Cs-alkyl and 5- to 8-membered heterocycloalkyl.
  • a method for the treatment of a bacterial or mycobacterial comprising the administration of a therapeutically effective amount of a compound of any one of clauses 1 to 15.
  • composition wherein the composition comprises a compound of any one of clauses 1 to 15 and one or more pharmaceutically acceptable excipients.
  • halo refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • Halo or “halogen” may refer to an atom selected from CI and F.
  • Halo or “halogen” may refer to fluorine.
  • alkyl refers to a linear or branched hydrocarbon chain.
  • C-i-Cs alkyl refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • C1-C6 alkyl refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • C1-C6 alkyl for example refers to methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • alkyl group may be substituted or unsubstituted by one or more substituents.
  • Substituents for the alkyl group may be halo (for example fluorine, chlorine, bromine and iodine), OH and C1-C6 alkoxy.
  • alkylene groups may be linear or branched and may have two places of attachment to the remainder of the molecule.
  • alkylene refers to a divalent group which is a linear or branched hydrocarbon chain. With the “alkylene” group being divalent, the group must form two bonds to other groups.
  • Ci-Cs-alkylene may refer to -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-,
  • alkylene group may be unsubstituted or substituted by one or more substituents.
  • cycloalkyl refers to a saturated hydrocarbon ring system.
  • C3-C8 cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indane.
  • cycloalkyl may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and indane.
  • the cycloalkyl group may be substituted with one or more substituents.
  • haloalkyi refers to a linear or branched hydrocarbon chain which is substituted with at least one halogen atom which is independently selected at each occurrence from fluorine, chlorine, bromine and iodine.
  • C1-C6 haloalkyi refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms. The halogen atom may be at substituted at any position on the hydrocarbon chain.
  • C1-C6 haloalkyi may refer to, for example, fluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl, trifluoroethyl, chloroethyl, trichloroethyl (such as 1 ,2,2-trichloroethyl and 2,2,2-trichloroethyl), fluoropropyl and chloropropyl.
  • the haloalkyi group may be substituted with one or more substituents.
  • alkenyl refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon double bond and having at least two carbon atoms.
  • C2-C6 alkenyl refers to a linear or branched hydrocarbon chain containing at least one carbon- carbon double bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the double bond or double bonds may be E or Z isomers. The double bond may be present at any possible position of the hydrocarbon chain.
  • C2-C6 alkenyl may refer to, for example, ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • the alkenyl group may be substituted or unsubstituted by one or more substituents.
  • cycloalkenyl refers to an unsaturated hydrocarbon ring system.
  • C3-C8 cycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the ring may contain more than one double bond.
  • cycloalkenyl may refer to, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloocatadienyl.
  • the cycloalkenyl group may be substituted with one or more substituents.
  • alkynyl refers to a linear or branched hydrocarbon chain contain at least one carbon-carbon triple bond and having at least two carbon atoms.
  • C2-C6 alkynyl refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond or triple bonds may be present at any possible position of the hydrocarbon chain.
  • C2-C6 alkynyl may refer to, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • the alkynyl group may be unsubstituted or substituted by one or more substituents.
  • heteroalkyi refers to a linear or branched hydrocarbon chain containing at least one heteroatom selected from N, O and S which is positioned between any possible carbon atom in the chain or at the end of the chain.
  • C1-C6 heteroalkyi refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S which is positioned between any possible carbon atom in the chain or at the end of the chain.
  • the heteroalkyi may be attached to another group by the heteroatom or the carbon atom.
  • C1-C6 heteroalkyi may refer to, for example, -CH2NHCH3, -NHCH2CH3 and -CH2CH2NH2.
  • the heteroalkyi group may be unsubstituted or substituted by one or more substituents.
  • heterocycloalkyi refers to a saturated hydrocarbon ring system containing at least one heteroatom within the ring system selected from N, O and S.
  • the term “5- to 8- membered heterocycloalkyi” refers to a saturated hydrocarbon ring with 5, 6, 7, 8, 9 or 10 atoms selected from carbon, N, O and S, at least one being a heteroatom.
  • the "heterocycloalkyi” group may also be denoted as a "3 to 10 membered heterocycloalkyi" which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one being a heteroatom.
  • the ring system may be a single ring or a bi-cyclic or tri-cyclic ring system.
  • Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon or nitrogen atoms; or they may share a bridgehead, i.e. the rings are linked to each other two non-adjacent carbon or nitrogen atoms.
  • the ring system is bicyclic one of the rings may be an aromatic ring, for example as in chromane.
  • the "heterocycloalkyi" may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the "heterocycloalkyi” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
  • the "heterocycloalkyi” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, and chromane.
  • heterocycloalkenyl refers to an unsaturated hydrocarbon ring system containing at least one heteroatom selected from N, O or S.
  • C3-C8 heterocycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom selected from N, O or S.
  • the double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom.
  • the ring system may be a single ring or a bi-cyclic or tri-cyclic ring system.
  • one of the rings may be an aromatic ring, for example as in indoline and dihydrobenzofuran.
  • the heterocycloalkenyl may be attached to another group by any carbon or heteroatom.
  • the term heterocycloalkenyl may refer to, for example tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene and indoline.
  • the heterocycloalkenyl group may be substituted with one or more substituents.
  • aryl refers to an aromatic hydrocarbon ring system which satisfies Huckel's rule for aromaticity or that contains a ring system which satisfies Huckel's rule for aromaticity.
  • an aryl group may be a single ring or a bi-cyclic or tri-cyclic ring system.
  • aryl may refer to, for example, phenyl, naphthyl, indane, tetralin and anthracene.
  • the aryl group may be unsubstituted or substituted with one or more substituents. Any aryl group may be a phenyl ring.
  • heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom selected from N, O or S which satisfies Huckel's rule for aromaticity or a ring system that contains a heteroatom and an aromatic hydrocarbon ring.
  • the heteroaryl may be a single ring system or a fused ring system.
  • the term "5-, 6-, 9- or 10- membered heteroaryl” refers to an aromatic ring system within 5, 6, 9, or 10 members selected from carbon, N, O or S either in a single ring or a bicyclic ring system.
  • heteroaryl may refer to, for example, imidazole, thiazole, oxazole, isothiazole, isoxazole, triazole, tetraazole, thiophene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, indole, isoindole, quinolone, and isoquinoline.
  • alkoxy refers to an alkyl group which is linked to another group by oxygen.
  • the alkyl group may be linear or branched.
  • C1-C6 alkoxy refers to an alkyl group containing 1 , 2, 3, 4, 5 or 6 carbon atoms which is linked to another group by oxygen.
  • the alkyl group may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl, n-pentyl and n-hexyl.
  • C1-C6 alkoxy may refer to, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • the alkyl group may be substituted or unsubstituted by one or more substituents.
  • a bond terminating in a " - r ⁇ r " means that the bond is connected to another group that is not shown.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.
  • a group may be substituted at any point on the group where chemically possible and consistent with valency requirements.
  • the group may be substituted by one or more substituents.
  • the group may be substituted with 1 , 2, 3 or 4 substituents. Where there are two or more substituents, the substituents may be the same or different.
  • Substituent(s) may be, for example, halo, CN, nitro, oxo, Ci-C6-alkyl, C2-C6-alkynyl, C 2 -C 6 -alkenyl, Ci-C 6 -haloalkyl, OR a , NR a R b , SR a , C(0)OR a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 OR a , S(0) 2 R a and S(0) 2 NR a R a ; wherein R a is independently at each occurrence selected from: H and Ci-C6-alkyl; and R b is independently at each occurrence selected from: H, d-Ce-alkyl, C(0)Ci-C 6 -alkyl and S(0) 2 -Ci-C 6 -alkyl.
  • a cyclic substituent may be substituted on a group so as to form a spiro-cycle.
  • ortho, meta and para substitution are well understood terms in the art.
  • "ortho" substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in " ".
  • Metal substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words, there is a substituent on the second atom away from the atom with another substituent.
  • the groups below are meta substituted.
  • Para substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words, there is a substituent on the third atom away from the atom with another substituent.
  • the groups below are para substituted.
  • the ion of formula (I) will be associated with a pharmaceutically acceptable anionic counter ion for administration to a subject. Nevertheless, where either the cation of formula (I) or the anionic counter ion comprise either basic or acidic groups, those groups may themselves be protonated or deprotonated and associated with an appropriate counter ion.
  • Suitable acid addition salts are formed from acids which form non-toxic salts, for example, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 1 ,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate,
  • Suitable base salts are formed from bases which form non-toxic salts, for example include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • the salt may be an acid addition salt.
  • the salts may be formate or hydrochloride.
  • compositions of formula (I) may be prepared by one or more of the following methods:
  • the reactions above are typically carried out in solution and the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non- ionised.
  • the compounds may exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Complexes are contemplated, such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • Complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts are also contemplated.
  • the resulting complexes may be ionised, partially ionised, or non- ionised.
  • radionuclides that may be incorporated include 2 H (also written as “D” for deuterium), 3 H (also written as "T” for tritium), 11 C, 13 C, 14 C, 15 0, 17 0, 18 0, 18 F and the like.
  • the radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro competition assays, 3 H or 14 C are often useful. For radio-imaging applications, 11 C or 18 F are often useful.
  • the radionuclide is 3 H.
  • the radionuclide is 14 C.
  • the radionuclide is 11 C.
  • the radionuclide is 18 F.
  • references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds include a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.
  • the compounds Before purification, the compounds may exist as a mixture of enantiomers depending on the synthetic procedure used.
  • the enantiomers can be separated by conventional techniques known in the art. Thus, the compounds cover individual enantiomers as well as mixtures thereof.
  • any compatible protecting radical can be used.
  • methods of protection and deprotection such as those described by T.W. Greene (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981 ) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.
  • the compounds as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
  • the compounds and formulations of the present invention can be used to treat both Gram-positive and Gram-negative bacterial infections such as infections of the genitourinary system, the respiratory tract, the gastrointestinal tract, the ear, the skin (including wounds), the throat, soft tissue, bone and joints.
  • the compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, tonsillitis, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, bacterial vaginosis, pelvic inflammatory disease, pseudomembranous colitis, acute gingivitis, Crohn's disease, rosacea, fungating tumours, impetigo.
  • the compounds can be used prophylactically, e.g. before surgery (including dental surgery).
  • the bacterial infection may be caused by Gram-positive bacteria (e.g. a strain of a Gram-positive bacteria that is resistant to an antibiotic).
  • the bacterial infection may be caused by a bacteria selected from: Staphylococcus aureus, Enterococcus faecium, Clostridium difficile and Streptococcus pneumonia.
  • the bacterial infection may be caused by Gram-negative bacteria (e.g. a strain of a Gram-negative bacteria that is resistant to an antibiotic).
  • the bacterial infection may be caused by a bacteria selected from Acinetobacter Baumannii, Pseudomonas aeruginosa, Enterobacteriaceae (a class of bacteria including Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp, Morganella spp), Helicobacter pylori, Campylobacter spp., Salmonella spp, Neisseria gonorrhoeae, Shigella spp. and Haemophilus Influenzae.
  • Acinetobacter Baumannii Pseudomonas aeruginosa
  • Enterobacteriaceae a class of bacteria including Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp, Morganella spp
  • the compounds of the invention can be used to treat mycobacterial infections, e.g. mycobacterial infections caused by resistant strains of mycobacteria. Thus, they can be used to treat TB or leprosy.
  • the compounds may be used to treat resistant strains of TB, e.g. MDR- TB (i.e. TB infections caused by strains which are resistant to isoniazid and rifampicin), XDR- TB (i.e. TB infections caused by strains which are resistant to isoniazid, rifampicin, at least one fluoroquinolone and at least one of kanamycin, capreomycin and amikacin) and/or TDR- TB (i.e. TB infections caused by strains which have proved resistant to every drug tested against it with the exception of a compound of the invention).
  • MDR- TB i.e. TB infections caused by strains which are resistant to isoniazid and rifampicin
  • XDR- TB i
  • the compounds of the invention may be used to treat infections caused by bacterial or mycobacterial strains that are resistant to at least one antibiotic.
  • the term 'resistant' is intended to refer to strains of bacteria or mycobacteria that have shown non-susceptibility to one or more known antibiotic drug.
  • a non-susceptible strain is one in which the MIC of a given compound or class of compounds for that strain has shifted to a higher number than for corresponding susceptible strains.
  • the term 'resistant' is used to mean a strain to such an extent that the use of the antibiotic in treating that strains is associated or is expected to be associated with a high likelihood of therapeutic failure.
  • the bacterial strain may be resistant to an antibiotic selected from: a fluoroquinolone, a ⁇ -lactam (e.g. penicillin, methicillin, ampicillin), a carbapenem, a cephalosporin, vancomycin, clarithromycin and azithromycin.
  • an antibiotic selected from: a fluoroquinolone, a ⁇ -lactam (e.g. penicillin, methicillin, ampicillin), a carbapenem, a cephalosporin, vancomycin, clarithromycin and azithromycin.
  • the compounds of the invention can be used to treat mycobacterial infections, e.g. mycobacterial infections caused by strains of mycobacteria that are resistant to an approved antimycobacterial agent. Thus, they can be used to treat TB or leprosy.
  • the compounds may be used to treat resistant strains of TB (e.g. strains which are resistant to at least one of isoniazid, rifampicin, a fluoroquinolone, kanamycin, capreomycin and amikacin).
  • the compounds of the invention may also be useful in treating other forms of infectious disease, e.g. fungal infections, parasitic infections and/or viral infections.
  • the compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.
  • the compound of the invention may be administered in combination with another antibiotic or with a compound that increases the effectiveness of an antibiotic.
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products may be administered so that the combination is provided in a therapeutically effective amount, for example the compounds of this invention may be administered within a therapeutically effective dosage range described herein and the other pharmaceutically-active agent may be administered in therapeutically effective amount, including in an amount of less than or within its approved dosage range.
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ⁇ g(microgram)/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
  • compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. [00139] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication (including the location of the infection in the body), age, and co-morbid medical conditions of the patient.
  • Certain ions of the invention can be synthesised according to or analogously to methods described in the General Schemes below and/by other techniques known to those of ordinary skill in the art. Certain ions of the invention can be synthesised according to or analogously to the methods described in the Examples.
  • Reductive amination of N-desmethyl-azithromycin (1 ) with aldehyde (2) can furnish amine (3), where LG represents a leaving group, such as CI, Br, I, tosyl or mesylate and L 6 is a Ci-Ci5-alkylene group.
  • the reaction can be accomplished using an appropriate reducing agent, such as NaBHsCN in the presence of a source of acid, such as CH3COOH, in an organic solvent, such as DMF, at a temperature of 25 to 80 °C.
  • Displacement of the LG in (3) with phosphine (4) can deliver phosphonium amine (5).
  • the reaction can be performed in an organic solvent such as MeCN, at a temperature of 50 to 90 °C.
  • a metal iodide such as Nal or Kl in the cases where the LG is not I can facilitate formation of the I in situ as a potentially more effective LG.
  • L 4 is a C3-Ci6-alkylene group. Removal of the cladinosyl sugar in phosphonium amine (6) to give phosphonium alcohol (7) can be accomplished using an acid, such as HCI in an alcoholic solvent, such as MeOH, at room temperature.
  • an acid such as HCI
  • an alcoholic solvent such as MeOH
  • UPLC/MS was carried out using a Waters Acquity QDa mass detector and Method A or Waters SQ mass detector and Methods B, C, D, E, F, I or Agilent 6120 MSD and Method G or Waters Xevo G2-XS Q-Tof and method H
  • Method H Column: Cortecs UPLC C18, 1 .6 m, 2.1 x 30 mm; Gradient Eluent: 5-95% MeCN/h O containing 0.1 % HCOOH; Time: 0-1.1 min
  • Ts para-toluenesulfonate
  • DMF ⁇ , ⁇ -dimethylformamide
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • DMSO dimethyl sulfoxide
  • Step 1 To a stirred solution of N-desmethyl-azithromycin (1 equivalent), LG-L6a- CHO (where LG presents a leaving group; L6a is one carbon shorter than L 6 ) (3.5
  • Step 2 The resulting purified product from step 1 is dissolved in MeCN (10 mL) and treated with the corresponding phosphine (3 equivalents) and Nal (3 equivalents). After thermal heating at 70 to 85 °C for 16 to 20 h the reaction mixture is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by chromatography to give the final desired product. As an adaptation, the reaction can be conducted under microwave conditions at 100 °C for 2 to 6 h.
  • Example 1 - ⁇ 8-(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4-
  • reaction mixture On cooling the reaction mixture was further stirred at room temperature. After 72 h the reaction mixture was partitioned between H 2 0 (100 mL), saturated aqueous NaHC0 3 (100 mL) and DCM (200 mL). The layers were separated and the aqueous further extracted with DCM (2 x 150 mL). The combined organics were washed with saturated aqueous NaHCOs (200 mL) and brine (3 X 200 m) and concentrated in vacuo.
  • Example 2 dicyclohexyl( ⁇ 6-[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 -
  • Example 5 tricyclohexy ie- ⁇ R.SS ⁇ R.SR.eR OR IR ⁇ S SS.MRM I - il ⁇ S.SR ⁇ S.eRH-idimethylaminoJ-S-hydroxy-e-met ⁇
  • Example 6 - ⁇ 8-(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy ⁇ -2-ethyl-3,4,10-trihydroxy-13- ⁇ [(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy ⁇ -3,5,8,10,12,14- hexamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-6-yl]octyl ⁇ ( ⁇ 2- [(dimethylamino)methyl]phenyl ⁇ )diphenylphosphonium iodide
  • Example 7 - ⁇ 8-(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy ⁇ -2-ethyl-3,4,10-trihydroxy-13- ⁇ [(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy ⁇ -3,5,8,10,12,14- hexamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-6-yl]octyl ⁇ [4- dimethylamino)phenyl]diphenylphosphonium iodide
  • Example 8 - ⁇ 8-(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy ⁇ -2-ethyl-3,4,10-trihydroxy-13- ⁇ [(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy ⁇ -3,5,8,10,12,14- hexamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-6-yl]octyl ⁇ tris(4- methoxyphenyl)phosphonium iodide
  • Example 9 - ⁇ [1 ,1 '-biphenyl]-2-yl ⁇ ( ⁇ 8-(2R,3S,4R,5R,8R,10R,11 R,12S,13S.14R)- 11 - ⁇ [(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy ⁇ -2-ethyl -3,4,10- trihydroxy-13- ⁇ [(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy ⁇ - 3,5,8,10,12,14-hexamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-6- yl]octyl ⁇ )diphenyl)phosphonium iodide
  • Example 10 - ⁇ 10-(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy ⁇ -2-ethyl-3,4,10-trihydroxy-13- ⁇ [(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy ⁇ -3,5,8,10,12,14- hexamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-6-yl]decyl ⁇ tris(4- methox henyl)phosphonium iodide
  • Example 11 - ⁇ 8-(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4- (dimethylamino)-3 -hydroxy -6-methyloxan-2-yl]oxy ⁇ -2 -ethyl -3, 4,10,13-tetrahydroxy- 3,5,8,10,12,14-hexamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-6-yl]octyl ⁇ tris(4- methoxyphenyl)phosphonium iodide
  • Example 12 - ⁇ 8-(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4- (dimethylamino)-3 -hydroxy -6-methyloxan-2-yl]oxy ⁇ -2 -ethyl -3, 4,10,13-tetrahydroxy- 3,5,8,10,12,14-hexamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-6-yl]octyl ⁇ [4- (dimethylamino)phenyl]diphenylphosphonium iodide
  • Example 13 e-I ⁇ R.SS ⁇ R.SR.eR OR IR ⁇ S SS.MRM HI ⁇ S.SR ⁇ S.eRM- idimethylaminoJ-S-hydroxy-G-methyloxan ⁇ -ylloxy ⁇ -ethyl ⁇
  • Example 16 (2- ⁇ 6-[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4- (dimethylamino)-3 -hydroxy -6-methyloxan-2-yl]oxy ⁇ -2 -ethyl -3,4,10-trihydroxy-13- ⁇ [(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy ⁇ -3,5,6,8,10,12,14- heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-4-yl N- methylhexanamido ⁇ ethyl)triphenylphosphonium bromide
  • reaction mixture was placed in a hydrogenation autoclave and purged with N2 (3x) followed by H2 (3x). The reaction mixture was then stirred at room temperature under H2 at 5 bar. After 16 h the reaction mixture was filtered through a pad of celite, which was washed with EtOH (20 mL).
  • the resulting reaction mixture was heated at 30 °C for 16 h. On cooling the reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCOs (5 mL) and H2O (10 mL). The combined aqueous extracts were back extracted with DCM (2 X 10 mL). The combined organic extracts were dried over Na2S0 4 and concentrated under reduced pressure. The resulting residue was purified by chromatography eluting with 0-10%
  • the minimum inhibitory concentration (MICs) versus planktonic bacteria are determined by the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard- 10 th Ed. CLSI document M7-A10, 2015).
  • the broth dilution method involves a two-fold serial dilution of compounds in 96-well microtitre plates, giving a final concentration range of 0.25-128 ⁇ g(micrograms)/mL and a maximum final concentration of 1 % DMSO.
  • the bacterial strains tested include the Gram-positive strains Staphylococcus aureus ATCC 29213, Staphylococcus aureus NRS 384, Streptococcus pneumoniae ATCC49619, Streptococcus pneumoniae 5174.00 and the Gram negative strains Acinetobacter baumannii ATCC BAA 747, Acinetobacter baumannii NCTC 13301 , Escherichia coli ATCC 25922, Escherichia coli ATCC BAA-2469, Klebsiella pneumoniae ATCC 43816, Klebsiella pneumoniae ATCC BAA-2146, Neisseria gonorrhoeae ATCC49226, Neisseria gonorrhoeae NCTC 13481 , Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa NCTC 13437.
  • Stock test compound solutions were prepared in sterile DMSO and diluted in the appropriate growth medium to provide a test range of 128 to 0.25 ⁇ g (micrograms)/ml_ and maximum final concentration of 1 % DMSO.
  • Doxycycline was prepared in sterile water.
  • Azithromycin was prepared in 95% EtOH.
  • Assay plates were incubated at 37 °C in air for 16 to 20 h, except for Streptococcus pneumoniae which was incubated for 20 to 24 h, and Neisseria gonorrhoeae which was incubated for 20 to 24 h under 5% CO2. Endpoints were determined visually (all assays) and by spectrophotometer at 600 nm (all assays except Streptococcus pneumoniae and Neisseria gonorrhoeae). The MIC is determined as the lowest concentration of test compound that completely inhibits visible growth of the bacteria and is reported in Table 1.
  • an MIC (in ⁇ g (micrograms)/ml_) of less or equal to 1 is assigned the letter A; a MIC of from 1 to 10 is assigned the letter B; a MIC of from 10 to 50 is assigned the letter C; a MIC of from 50 to 100 assigned the letter D; and a MIC of over 100 is assigned the letter E.
  • the compounds of the invention all showed activity against bacterial pathogens.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés qui peuvent être utilisés pour traiter des infections bactériennes. Les composés comprennent des dérivés d'azithromycine ayant un cation phosphonium attaché au macrocycle d'azithromycine. L'invention concerne également des procédés d'utilisation desdits composés et des formulations pharmaceutiques comprenant lesdits composés. Les composés comprennent un ion de formule (I) : R 5 est indépendamment choisi parmi H, un alkyle en C(O)-C1 -C6 ou R 5 a la structure : (ll)
PCT/EP2018/060244 2017-04-20 2018-04-20 Dérivés d'azithromycine contenant un ion phosphonium utilisés en tant qu'agents antibactériens Ceased WO2018193124A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1706299.3A GB201706299D0 (en) 2017-04-20 2017-04-20 Compounds
GB1706299.3 2017-04-20

Publications (1)

Publication Number Publication Date
WO2018193124A1 true WO2018193124A1 (fr) 2018-10-25

Family

ID=58795591

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/060244 Ceased WO2018193124A1 (fr) 2017-04-20 2018-04-20 Dérivés d'azithromycine contenant un ion phosphonium utilisés en tant qu'agents antibactériens

Country Status (2)

Country Link
GB (1) GB201706299D0 (fr)
WO (1) WO2018193124A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0941998A2 (fr) * 1998-03-03 1999-09-15 Pfizer Products Inc. Antibiotiques macrolides de type 3,6-cétal et éther d'énol
WO2004101590A1 (fr) * 2003-05-13 2004-11-25 Glaxo Group Limited Nouveaux composes a cycles a 14 et 15 elements

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0941998A2 (fr) * 1998-03-03 1999-09-15 Pfizer Products Inc. Antibiotiques macrolides de type 3,6-cétal et éther d'énol
WO2004101590A1 (fr) * 2003-05-13 2004-11-25 Glaxo Group Limited Nouveaux composes a cycles a 14 et 15 elements

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KANAZAWA A ET AL: "Synthesis and antimicrobial activity of dimethyl- and trimethyl-substituted phosphonium salts with alkyl chains of various lengths", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 38, no. 5, 1 May 1994 (1994-05-01), pages 945 - 952, XP002554246, ISSN: 0066-4804 *
YAN XUE ET AL: "Antimicrobial Polymeric Materials with Quaternary Ammonium and Phosphonium Salts", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 16, no. 2, 6 February 2015 (2015-02-06), pages 3626 - 3655, XP055493340, DOI: 10.3390/ijms16023626 *

Also Published As

Publication number Publication date
GB201706299D0 (en) 2017-06-07

Similar Documents

Publication Publication Date Title
WO2021063346A1 (fr) Inhibiteur de kras g12c et application associée
US10385065B2 (en) Antibacterial compounds
DE69333223T2 (de) Bicyclische Aminderivate
AU2021268845A1 (en) Compounds as Bcl-2 inhibitors
EP4216940A1 (fr) Dérivés de pyrido[4,3-b]indole et leur utilisation comme produits pharmaceutiques
JP6929881B2 (ja) 新規なβ−ラクタマーゼ阻害剤
EP3856743A1 (fr) Composés imidazo [1, 2-a] pyridine et [1, 2, 4] triazolo [1, 5-a] pyridine substitués en tant qu'inhibiteurs de kinase ret
WO1992021659A1 (fr) Derive d'acide pyridonecarboxylique
US20160347762A1 (en) Aryl substituted aminomethyl spectinomycin analogs as antibacterial agents
WO2018193124A1 (fr) Dérivés d'azithromycine contenant un ion phosphonium utilisés en tant qu'agents antibactériens
JPH02290870A (ja) 対掌体的に純粋な７‐（３‐アミノ‐１‐ピロリジニル）‐キノロン‐および‐ナフチリドンカルボン酸
WO2023231777A1 (fr) Composés en tant qu'inhibiteurs de bcl-2
CN102040591B (zh) 7-苯基喹诺酮类化合物
CN117510561A (zh) 一种泰乐菌素衍生物及其制备方法与应用
KR100458146B1 (ko) 사이클로알킬아미노메틸피롤리딘유도체및이를유효성분으로하는항생제
ES2968733T3 (es) Derivados morfolinilo, piperazinilo, oxazepanilo y diazepanilo útiles como inhibidores de o-glicoproteína-2-acetamido-2-desoxi-3-d-glucopiranosidasa
WO2018193126A1 (fr) Dérivés d'azithromycine contenant un ion phosphonium en tant qu'agents antibactériens
JPH051073A (ja) 光学活性ピリドベンゾオキサジン誘導体
EP3414245A1 (fr) Composés antibactériens
WO2024032755A1 (fr) Composés en tant qu'inhibiteurs de bcl-2
TW201309689A (zh) 含胺基之吡咯啶酮衍生物
JP4926723B2 (ja) フルオロアルキルピロリジン誘導体
CN102329315A (zh) 含有氟甲氧亚氨基取代的萘啶酮羧酸类化合物及其制备方法
WO2011031743A1 (fr) Analogues de fluoroquinolone antibactériens
WO2016123146A1 (fr) Composés pontés pour le traitement des infections bactériennes

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18721716

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18721716

Country of ref document: EP

Kind code of ref document: A1