WO2010025906A2 - Hybrid antimicrobial compounds and their use - Google Patents

Hybrid antimicrobial compounds and their use Download PDF

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Publication number
WO2010025906A2
WO2010025906A2 PCT/EP2009/006359 EP2009006359W WO2010025906A2 WO 2010025906 A2 WO2010025906 A2 WO 2010025906A2 EP 2009006359 W EP2009006359 W EP 2009006359W WO 2010025906 A2 WO2010025906 A2 WO 2010025906A2
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Prior art keywords
independently
present
compound according
optionally substituted
optionally
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PCT/EP2009/006359
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French (fr)
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WO2010025906A3 (en
Inventor
Harald Labischinski
Joseph Cherian
Cleofe Calanasan
Rustum S. Boyce
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Merlion Pharmaceuticals Pte Ltd
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Publication of WO2010025906A2 publication Critical patent/WO2010025906A2/en
Publication of WO2010025906A3 publication Critical patent/WO2010025906A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
    • 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
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain antimicrobial compounds comprising pharmacophores based on or comprising benzyl pyrimidines and 4-quinolones or 4H-4-oxoquinolizines (for convenience, collectively referred to herein as "BP-4Q compounds”), which, inter alia, are antimicrobial, particularly antibacterial.
  • BP-4Q compounds 4-quinolones or 4H-4-oxoquinolizines
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to provide an antimicrobial function, particularly an antibacterial function, and in the treatment of diseases and conditions that are mediated by microbes, particularly bacteria, that are ameliorated by the antimicrobial function, particularly an antibacterial function, including bacterial diseases, optionally in combination with another agent, for example, another antibacterial agent.
  • DHFR or Dihydrofolate Reductase is a constitutive enzyme that is specific to bacterial, parasitic and epithelial cells. It reduces dihydrofolate to tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidine acid and certain amino acids. Inhibitors of this enzyme have been used as antibiotics, antimalarial and chemotherapeutic agents. Examples of DHFR inhibitors as antibiotics are Trimethoprim (TMP), brodimoprim, methoprim and etioprim. TMP for example is a widely used antibiotic and is administered orally. It exhibits broad- spectrum antibacterial activity and excellent tolerability. However, bacterial resistance is a problem.
  • Quinolones are a group of broad spectrum antibiotics that act by inhibiting the bacterial DNA gyrase or topoisomerase IV enzyme thereby inhibiting DNA replication and transcription.
  • DNA gyrase is the target while DNA topoisomerase IV is the target for gram positive bacteria.
  • Eukaryotic cells do not contain DNA gyrase or topoisomerase.
  • the 4-quinolones comprise two types of structures, those with a fluorine atom mainly at C6 (known as Fluoroquinolones, which include the majority of quinolones in clinincal use) and those without.
  • Therapeutically useful quinolones may be divided into two groups, quinolone or 1 , 8- naphthyridone and those with a tricyclic nucleus of the 6, 7 type (oxolinic acid) and of the 1 , 8 type (ofloxacin, levofloxacin.etc).
  • Ciprofloxacin (CIP) is a well known example of a fluoroquinolone. Like TMP it is a widely used orally administered antibiotic with broad-spectrum antibacterial activity but, again like TMP, it also encounters bacterial resistance.
  • 4H-4-oxoquinolizines are a comparatively new addition to the quinolone family, in which nitrogen replaces the carbon between ring carbons C-4 and C-5. They have been used to overcome bacterial resistance to fluoroquinolones. They exhibit antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone- resistant MRSA.
  • Combination therapies comprising administering two antibiotics have been investigated, for example the combination of TMP and CIP (see, Huovinen et ah, 1992); however the different pharmacokinetic behaviour of the two antibiotics means that there remains a problem of delivering the individual components to the site of infection at the same time and for a sufficient time so that effective treatment can occur.
  • Hybrid antibiotics comprise two molecules having antibacterial activity linked covalently.
  • the covalent linker is important in achieving the desired activity and the mere selection of a second antibacterial as a substituent on a first antibacterial molecule will not guarantee activity (see e.g. WO96/16046).
  • the hybrid antibacterial approach combines molecules with targets in different bacterial target pathways (e.g. DNA-replication and cell wall biosynthesis, DNA replication and protein biosynthesis) (see e.g. WO2005/070940 and US2006019986).
  • the primary aim of the hybrid approach has been to overcome resistance by addressing two targets.
  • One aspect of the invention pertains to certain hybrid antibiotic compounds comprising linked benzyl pyrimidines (BP) (e.g. trimethoprim) and 4-quinolones or 4H-4-oxoquinolizines (4Q) (e.g. fluoroquinolone) as described herein.
  • BP linked benzyl pyrimidines
  • 4Q 4-quinolones or 4H-4-oxoquinolizines
  • BP-4Q compounds For convenience, these compounds are collectively referred to herein as "BP-4Q compounds”.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a BP-4Q compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising the step of admixing a BP-4Q compounds, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention pertains to a method of killing microbes in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein.
  • the present invention is concerned with providing an antimicrobial action (e.g. an antibacterial and/or antifungal action).
  • Another aspect of the present invention pertains to a method of inhibiting (e.g. reducing or preventing) growth or reproduction of bacteria, killing bacteria, or a combination of both these, in vitro or in vivo, comprising contacting a host with an effective amount of a BP-4Q compound, as described herein.
  • the method further comprises contacting the host with one or more other antibacterial agents.
  • Another aspect of the present invention pertains to a method of killing bacteria in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein.
  • the method further comprises contacting the host with one or more other antibacterial agents.
  • Another aspect of the present invention pertains to a bacteriocidal method using an effective amount of a BP-4Q compound.
  • Another aspect of the present invention pertains to a method of reducing or preventing the growth or reproduction of bacteria in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein.
  • Another aspect of the present invention pertains to a bacteriostatic method using an effective amount of a BP-4Q compound.
  • the method further comprises contacting the host with one or more other antibacterial agents.
  • BP-4Q compound as described herein, preferably in the form of a pharmaceutical composition.
  • the method further comprises administering to the subject one or more other antibacterial agents.
  • Another aspect of the present invention pertains to a BP-4Q compound as described herein for use in a method of treatment of the human or animal body by therapy.
  • the method of treatment comprises treatment with both (i) a BP- 4Q compound as described herein and (ii) one or more other antibacterial agents.
  • Another aspect of the present invention pertains to use of a BP-4Q compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment comprises treatment with both (i) a medicament comprising a BP-4Q compound as described herein and (ii) one or more other antibacterial agents.
  • the treatment is treatment of a disease or condition that is mediated or caused by bacteria.
  • the treatment is treatment of a disease or condition that is ameliorated by the inhibition of bacteria growth or reproduction and/or bacteria death.
  • the treatment is treatment of a bacterial infection.
  • the treatment is treatment of a bacterial disease.
  • kits comprising (a) a BP-4Q compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • the kit further comprises one or more other antibacterial agents.
  • Another aspect of the present invention pertains to a BP-4Q compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to a BP-4Q compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to a method of synthesis of a BP-4Q compound, as described herein.
  • features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.
  • One aspect of the present invention relates to certain hybrid antibiotic compounds comprising a benzyl pyrimidine linked to a 4-quinolone or 4H-4-oxoquinolizine (for convenience, collectively referred to herein as "BP-4Q compounds").
  • BP-4Q compounds Benzyl pyrimidines (BP) and 4-quinolones (4Q) are represented below by trimethoprim (TMP) and ciprofloxacin (CIP).
  • the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof: NH,
  • each of -R 1 and -R 3 is independently -OR A
  • -R 2 is independently -Br or -OR A
  • each -R A is independently saturated aliphatic C1-4 alkyl or -L-A
  • -L- is independently -L 1 -L 2 - or -L 2 -
  • -L 1 - is independently -L 1C - or -L 1H -
  • -L 2 - is independently -L 2H - or -L 2 *-
  • -L 1C - is independently saturated aliphatic alkylene and is optionally substituted
  • -L 1H - is independently -L 1 S -L 1C -L 1Z - or -L 1c -L 1z -L 1c -,
  • -L 1Z - is independently -O-, -NR L1Z - or -NC(O)R L1Z -,
  • -R L1Z - is independently -H, saturated or unsaturated aliphatic Ci- ⁇ alkyl, or ( ⁇ noaryl, and is optionally substituted,
  • -L 2H - is independently saturated or unsaturated C4-7 heterocyclylene and is optionally substituted
  • R L2X is independently saturated or unsaturated aliphatic d ⁇ alkyl and is optionally substituted
  • -A is independently a 4-quinolonyl or 4H-4-oxoquinolizinyl.
  • a 4-quinolonyl is a monovalent radical formed by removal of a hydrogen atom or other substituent from a 4-quinolone.
  • the term "4-quinolone" as used herein includes 1 ,8-naphthyridones.
  • a 4H-4-oxoquinolizinyl is a monovalent radical formed by removal of a hydrogen atom or other substituent from a 4H-4-oxoquinolizine.
  • C 4 -/ in terms such as "C-wheterocyclylene” refer to the number of ring atoms, whether carbon atoms or heteroatoms.
  • cyclohexylene, piperidinylene, pyridinylene and piperazinylene are example of a C ⁇ cyclylene group.
  • each of -R 1 and -R 3 is independently -OR A .
  • -R 1 is independently -OR A .
  • -R 3 is independently -OR A .
  • -R 2 is independently -Br or -OR ⁇
  • -R 2 is independently -Br.
  • -R 2 is independently -OR A .
  • each -R A is independently saturated aliphatic d ⁇ alkyl or -L-A.
  • each -R A is independently saturated aliphatic Ci-4alkyl.
  • each -R A is independently -L-A.
  • each -R A is independently saturated aliphatic Ci- 2 alkyl.
  • each -R A is -Me.
  • -L- is independently -L 1 -L 2 - or -L 2 -.
  • -L- is independently -L 1 -L 2 -.
  • -L- is independently -L 2 -.
  • -L 1 - is independently -L 1C - or -L 1H -.
  • -L 1 - is independently -L 1C -.
  • -L 1 - is independently -L 1H -.
  • -L 1C - is independently saturated or unsaturated aliphatic Ci -4 alkylene and is optionally substituted.
  • -L 1 c - is independently saturated aliphatic Ci-4alkylene and is optionally substituted.
  • -L 1 c - is independently saturated aliphatic d ⁇ alkylene and is optionally substituted.
  • -L 1 c - is independently saturated aliphatic Ci- 2 alkylene and is optionally substituted.
  • -L 1 c - is independently saturated aliphatic C 2 alkylene and is optionally substituted.
  • -L 1 C - is independently aliphatic Cialkylene and is optionally substituted.
  • -L 1C - is independently -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, - CH 2 -C(CHa) 2 - or -CH 2 -CH 2 -CH 2 -.
  • -L 1C - is independently -CH 2 -.
  • -L 1C - is independently -CH 2 -CH 2 -.
  • -L 1C - is independently -CH(CH 3 )-CH 2 .
  • -L 1 S if present, is independently -CH 2 -C(CH 3 ) 2 -.
  • -L 1C - if present, is independently -CH 2 -CH 2 -CH 2 -.
  • -L 1H - is independently -L 1Z - , -L 1C -L 1Z - or -L 1C -L 1Z -L 1C -.
  • -L 1H - is independently -L 1Z -.
  • -L 1H - is independently -L 1C -L 1Z -.
  • -L 1H - is independently -L 1C -L 1Z -L 1C -.
  • -L 1Z - is independently -O-, -NR L1Z - or -NC(O) R L1Z -.
  • -L 1Z - if present, is independently -O-.
  • -L 1Z - if present, is independently -NR L1Z -.
  • -L 1Z - is independently -NC(O)R L1Z -.
  • -R L1Z - is independently -H, saturated or unsaturated aliphatic Ci- 6 alkyl, or C4-ioaryl, and is optionally substituted.
  • -R L1Z - is independently -H.
  • -R L1Z - is independently saturated or unsaturated aliphatic Ci-
  • -R L1Z - is independently C-noaryl, and is optionally substituted.
  • -R L1Z - is independently saturated aliphatic d ⁇ alkyl, and is optionally substituted.
  • -R L1Z - is independently C 6 aryl, and is optionally substituted.
  • -L 2 - is independently -L 2H - or L 2 *-.
  • -L 2 - if present, is independently -L 2H -.
  • -L 2 - if present, is independently -L 2 *-.
  • -L 2H - is independently saturated or unsaturated C 4 - 7 heterocyclylene and is optionally substituted.
  • -L 2H - is independently saturated or unsaturated C 4 .
  • ⁇ heterocyclylene is optionally substituted.
  • -L 2H - is independently saturated or unsaturated C 5 . ⁇ heterocyclylene and is optionally substituted.
  • -L 2H - is independently saturated alicyclic C 4 heterocyclylene and is optionally substituted.
  • -L 2H - is independently saturated alicyclic Csheterocyclylene and is optionally substituted.
  • -L 2H - is independently saturated alicyclic C 6 heterocyclylene and is optionally substituted.
  • -L 2H - is independently saturated or unsaturated C 4 .
  • -L 2H - is independently saturated or unsaturated C 4 .
  • -L 2H - is independently saturated or unsaturated C 4 . sheterocyclylene wherein one ring atom is N, and is optionally substituted.
  • -L 2H - is independently saturated or unsaturated C 5 - ⁇ heterocyclylene wherein one ring atom is N, and is optionally substituted.
  • -L 2H - is independently saturated alicyclic C 4 heterocyclylene wherein one ring atom is N, and is optionally substituted.
  • -L 2H - is independently saturated alicyclic Csheterocyclylene wherein one ring atom is N, and is optionally substituted.
  • -L 2H - is independently saturated alicyclic C ⁇ heterocyclylene wherein one ring atom is N, and is optionally substituted.
  • -L 2H - is independently saturated or unsaturated C 4 - ⁇ heterocyclylene wherein two ring atoms are N, and is optionally substituted.
  • -L 2H - is independently saturated or unsaturated C ⁇ heterocyclylene wherein two ring atoms are N, and is optionally substituted.
  • -L 2H - is independently saturated alicyclic C ⁇ heterocyclylene wherein two ring atoms are N, and is optionally substituted.
  • -L 2H - is independently a divalent group derived from azetidine, pyrrolidine, piperidine or piperazine, and is optionally substituted.
  • -L 2H - is independently azetidinylene , pyrrolidinylene , piperidinylene , or piperazinylene , and is optionally substituted.
  • -L 2H - is independently azetidinylene, and is optionally substituted.
  • -L 2H - is independently pyrrolidinylene, and is optionally substituted.
  • -L 2H - is independently piperidinylene, and is optionally substituted.
  • -L 2H - is independently piperazinylene, and is optionally substituted.
  • -L 2H - is independently bonded through a heteroatom of the heterocyclylene.
  • -L 2H - is independently bonded through two heteroatoms of the heterocyclylene.
  • -R 1 - 2 ⁇ is independently -CH 2 -NH 2 .
  • -R 1 - 2 ⁇ is independently -OH.
  • -R 12 "* is independently -CH 2 -NH 2 or -OH.
  • -R 12 "* is independently -CH 2 -NH 2 .
  • -R 12 "* is independently -OH.
  • -L 2 *- is independently wherein R L2X , if present, is independently saturated or unsaturated aliphatic and is optionally substituted.
  • -R L2X - 1 if present, is saturated or unsaturated aliphatic C1-4 alkyl and is optionally substituted.
  • -R 1 - 2 *- is saturated aliphatic d. 2 alkyl and is optionally substituted.
  • -R 12 *- if present, is Ci alkyl and is optionally substituted.
  • -R 12 *- if present, is -CH 2 -NH 2 .
  • -A is independently 4-quinolonyl or 4H-4-oxoquinolizinyl.
  • -A is independently 4-quinolonyl.
  • -A is independently 4H-4-oxoquinolizinyl.
  • -A is independently 4-quinolon-7-yl or 4H-4-oxoquinolizin-8-yl.
  • -A is independently fluoro-4-quinolonyl.
  • -A is independently 6-fluoro-4-quinolonyl.
  • -A is independently fluoro-4H-4-oxoquinolizinyl.
  • -A is independently 7-fluoro-4H-4-oxoquinolizinyl.
  • -A is independently -A 1 or -A 2 .
  • -A is independently -A 1 .
  • -A is independently -A 2 .
  • -A 1 is independently
  • each of Q 2 , Q 6 and Q 8 is independently C or N;
  • -R Q1 is independently cyclopropyl, saturated aliphatic d ⁇ alkyl, phenyl, pyridinyl, and is optionally substituted, or (a) together with -R Q8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C ⁇ eheterocycle and is optionally substituted, or (b) together with -R Q2 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C 4 - 6 heterocycle and is optionally substituted;
  • -R Q2 if present, and if Q 2 is C, is independently -H or together with -R Q1 and the atoms to which they are connected forms a saturated or unsaturated alicyclic C ⁇ heterocycle and is optionally substituted;
  • -R Q5 if present, is independently -H, -Me, or -NH 2 ;
  • -R 06 if present, and if Q 6 is C, is independently -H or -F, or together with -R 07 , if present, and the atoms to which they are attached forms a saturated or unsaturated alicyclic C ⁇ heterocycle, and is optionally substituted;
  • -R Q8 if present, and if Q 8 is C, is independently -H, -F, -Cl, -OMe, -OCH 2 F, -OCHF 2 , -OCF 3 , -CF 3 , -CN or together with -R Q1 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C ⁇ heterocycle, and is optionally substituted
  • each of Q 2 , Q 6 and Q 8 is independently C or N.
  • Q 2 is independently C or N.
  • Q 6 is independently C or N.
  • Q 8 is independently C or N.
  • Q 2 is independently C.
  • Q 2 is independently N.
  • Q 6 is independently C.
  • Q 6 is independently N.
  • Q 8 is independently C.
  • Q 8 is independently N.
  • -R Q1 is independently cyclopropyl, saturated aliphatic Chalky!, phenyl, pyridinyl, and is optionally substituted, or (a) together with -R Q8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic and is optionally substituted, or (b) together with -R 02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C ⁇ heterocycle and is optionally substituted.
  • -R Q1 is independently cyclopropyl, and is optionally substituted.
  • -R Q1 is independently saturated aliphatic d ⁇ alkyl and is optionally substituted.
  • -R Q1 is independently phenyl and is optionally substituted.
  • -R Q1 is independently pyridinyl, and is optionally substituted.
  • -R Q1 independently (a) together with -R Q8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C 4 - 6 heterocycle and is optionally substituted.
  • -R Q1 independently (b) together with -R 02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C ⁇ heterocycle and is optionally substituted.
  • -R Q1 is independently cyclopropyl, -CH 2 -CH 3 , -CH 2 -CH 2 F, or difluorophenyl.
  • -R° 2 if present, and if Q 2 is C, is independently -H or together with -R 01 and the atoms to which they are attached forms a saturated or unsaturated alicyclic C 4 heterocycle and is optionally substituted.
  • -R Q2 if present, and if Q 2 is C, is independently -H.
  • -R Q2 if present, and if Q 2 is C, independently together with -R Q1 and the atoms to which they are connected forms a saturated alicyclic C 4 heterocycle and is optionally substituted.
  • -R Q2 if present, and if Q 2 is C, independently together with -R Q1 and the atoms to which they are connected forms:
  • -R Q5 if present, is independently -H, -Me, or -NH 2 .
  • -R 05 if present, is independently -H.
  • -R Q5 if present, is independently -Me.
  • -R QS if present, is independently -NH 2 .
  • -R 06 if present, and if Q 6 is C, is independently -H or -F, or together with
  • -R Q6 if present, and if Q ⁇ is C, is independently -F.
  • -R Q6 if present, and if Q 6 is C, is independently -H.
  • -R Q6 if present, and if Q 6 is C, independently together with -R 07 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C 4 - ⁇ heterocycle, and is optionally substituted.
  • -R Q6 if present, and if Q 6 is C, independently together with -R Q7 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic Csheterocycle, and is optionally substituted.
  • -R Q6 if present, and if Q 6 is C, independently together with -R Q7 and the atoms to which they are attached, forms:
  • -R Q8 if present, and if Q 8 is C, is independently -H, -F, -Cl, -OMe, -
  • -R 08 if present, and if Q 8 is C, is independently -H.
  • -R 08 if present, and if Q 8 is C, is independently -F.
  • -R Q8 if present, and if Q 8 is C, is independently -Cl.
  • -R 08 if present, and if Q 8 is C, is independently -OMe.
  • -R Q8 if present, and if Q 8 is C, is independently -OCH 2 F.
  • -R Q8 , if present, and if Q 8 is C is independently -OCHF 2 .
  • -R Q8 if present, and if Q 8 is C, is independently -OCF 3 .
  • -R Q8 if present, and if Q 8 is C, is independently -CF 3 .
  • -R 08 if present, and if Q 8 is C, is independently -CN.
  • -R Q8 if present, and if Q 8 is C, independently together with -R Q1 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C 4 . eheterocycle and is optionally substituted.
  • -A 2 is independently
  • -X- if present, is independently -X 1 -, -X 2 - or -X 3 -
  • -X 1 - is independently cyclopropylene, and is optionally substituted
  • -X 2 - is independently saturated aliphatic C 2 alkylene and is optionally substituted
  • -X 3 - is independently C 6 arylene, and is optionally substituted
  • -R 07 is independently -R Q7A , -R Q7B , or -R Q7C , or together with -R Q6 and the atoms to which they are attached forms a saturated or unsaturated alicyclic and is optionally substituted;
  • -R Q7A if present, is independently C 6 aryl, and is optionally substituted;
  • -R Q7B if present, is independently saturated alicyclic Cs-ioheterocyclyl, and is optionally substituted;
  • -R Q7C is independently -H or -Me
  • -X- is independently -X 1 -, -X 2 - or -X 3 -.
  • -X- if present, is independently -X 1 -.
  • -X- is independently -X 2 -.
  • -X- if present, is independently -X 3 -.
  • -X 1 - is independently cyclopropylene, and is optionally substituted.
  • -X 1 - is independently cyclopropylene, and is optionally substituted.
  • -X 2 - is independently saturated aliphatic C 2 alkylene and is optionally substituted.
  • -X 2 - is independently -CH 2 -CH 2 -.
  • .-X 3 - is independently C ⁇ arylene, and is optionally substituted.
  • .-X 3 - is independently phenylene, and is optionally substituted.
  • the Group -R Q7 is independently C ⁇ arylene, and is optionally substituted.
  • -R 07 is independently -R Q7A , -R Q7B , or -R Q7C , or together with - R 06 and the atoms to which they are attached forms a saturated or unsaturated alicyclic C ⁇ heterocycle, and is optionally substituted.
  • -R 07 if present, is independently -R Q7A .
  • -R Q7 if present, is independently -R Q7B .
  • -R 07 if present, is independently -R Q7C .
  • -R 07 if present, independently together with -R Q6 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C ⁇ heterocycle, and is optionally substituted.
  • -R Q7 if present, independently together with -R Q6 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C 5 heterocycle, and is optionally substituted.
  • -R Q7 if present, independently together with -R Q6 and the atoms to which they are attached, forms:
  • -R Q7A is independently C 6 aryl, and is optionally substituted.
  • -R Q7A is independently phenyl, and is optionally substituted.
  • -R Q7A is independently
  • -R Q7B is independently saturated or unsaturated alicyclic Cs- t oheterocyclyl, and is optionally substituted.
  • -R Q7B is independently saturated or unsaturated alicyclic C 5 - ⁇ heterocyclyl, and is optionally substituted.
  • -R Q7B is independently piperidino, piperazino or pyrrolidino, and is optionally substituted.
  • -R Q7C is independently -H or -Me.
  • R A is optionally substituted with one or more substituents, -R S1 .
  • R L2X is optionally substituted with one or more substituents, -R S1 .
  • each R S1 is independently selected from:
  • each R S1 is independently selected from:
  • each R S1 if present, is independently selected from -R 531 .
  • -L 2H - is optionally substituted with one or more substituents, -R S2 .
  • each R S2 is independently selected from:
  • each R S2 is independently selected from:
  • each R S2 is independently selected from:
  • each R S2 is independently selected from:
  • -R Q1 is optionally substituted with one or more substituents, -R 33 .
  • each R S3 is independently selected from:
  • -R Q2 - is optionally substituted with one or more substituents, - R 34 .
  • -R Q6 - is optionally substituted with one or more substituents, - R 34 .
  • -R Q7 - is optionally substituted with one or more substituents, - R 34 .
  • -R Q8 - is optionally substituted with one or more substituents, - R 34 .
  • each R 34 is independently selected from: -F, -Cl, -Br, -I 1 or -OH
  • -X 3 - is optionally substituted with one or more substituents, -R S5 .
  • each R S5 is independently selected from:
  • -R Q7A - is optionally substituted with one or more substituents, - R 36 .
  • each -R 36 is independently selected from:
  • -R Q7A - is optionally substituted with one or more substituents, - R S7 .
  • each R S7 is independently selected from:
  • each -R SS1 is independently saturated aliphatic Ci- ⁇ alkyl.
  • each -R SS1 is independently saturated aliphatic Ci-3alkyl.
  • each -R SS1 is independently -Me.
  • each -L SS1 - is independently -(CH 2 J n -, wherein n is independently 1 to 4.
  • each -L SS1 - is independently -CH 2 - or -CH 2 CH 2 -.
  • the BP-4Q compounds as described herein combine two pharmacophores, both of which share a single target area (DNA synthesis), but each addresses independent individual steps in that target area.
  • This novel approach of targeting different steps in the same target system may provide a synergistic effect in terms of efficacy.
  • combining the two pharmacophores in the hybrid molecule suitably addresses some or all of the difficulties associated with the different pharmacokinetic behaviour of the two antibiotics such that the individual components can be delivered to the site of infection at the same time and for a sufficient time so that effective treatment can occur.
  • the benefits of the overall approach include one or more of low resistance selection propensity, activity against strains with resistance against one of the pharmacophores, and reduced susceptibility to efflux pump mechanism.
  • Another advantage could be that the toxicity of either or both of the component antibiotics is reduced in the combined hybrid antibiotic.
  • -R 2 is -O-L-A.
  • -L- is -U-L 2 - or -L 2 -; -L 1 -, if present, is -L 1H - and -L 2 - is -L 2H -.
  • -L- is independently selected from:
  • -L- is independently
  • -L- is independently
  • -L- is -L 2 - and -L 2 - is -L 2 "-.
  • -L 2X - is independently
  • -L- is -L 1 -L 2 -
  • -L 1 - is -L 1C -
  • -L 2 - is -L 2N -.
  • -L- is -L 1 -L 2 - and -L 1 - is -L 1C -.
  • -L 1C - is independently -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, -CH 2 - C(CH 3 J 2 - or -CH 2 -CH 2 -CH 2 -.
  • -L 1C - is independently -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, -CH 2 - C(CHs) 2 - or -CH 2 -CH 2 -CH 2 - and -L 2 - is -L 2H -.
  • -L 1C - is independently -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, -CH 2 - C(CH 3 );.- or -CH 2 -CH 2 -CH 2 -; -L 2 - is -L 2H -; and -L 2H - is independently saturated or unsaturated C 4 ⁇ heterocyclylene wherein one or more ring atoms are N, and is optionally substituted.
  • -L- is -L 1 -L 2 -; -L 1 - is -L 1C -L 1Z -L 1C -; and -L 1C -L 1Z -L 1C - is independently -CH 2 -CH 2 -O-CH 2 -CH 2 -.
  • -A is -A 1 .
  • -A 1 is independently selected from:
  • -A is -A 2 .
  • -A 2 is independently selected from:
  • each of -R 1 and -R 3 is independently -OR'
  • -R 2 is independently -Br or -OR ⁇
  • -R A is independently saturated aliphatic C1-4 alkyl or -L-A;
  • -L- is independently -L 1 -L 2 - or -L 2 -
  • -L 1 - is independently -L 1C - or -L 1H -
  • -L 2 - is independently -L 2H - or -L 2 *- wherein:
  • -L 1C - is independently saturated aliphatic C1-4 alkylene and is optionally substituted
  • -L 1H - is independently -L 1Z -, -L 1C -U Z - or -L 1C -L 1Z -L 1C -,
  • -L 1Z - is independently -O-, -NR L1Z - or
  • -R L1Z - is independently -H, saturated or unsaturated aliphatic Ci- ⁇ alkyl, or C-noaryl, and is optionally substituted,
  • -L 2H - is independently saturated or unsaturated C 4 -? heterocyclylene and is optionally substituted
  • R L2X is independently saturated or unsaturated aliphatic d. 4 alkyl and is optionally substituted
  • -A is independently a 4-quinolonyl or 4H-4-oxoquinolizinyl.
  • a compound according to any one of 1 to 37, wherein -L 2H -, if present, is independently selected from the following, wherein, if present, -R 12 "* is independently -CH 2 -NH 2 , -OH or N-OH and R 2LHB is independently -CH 2 -NH 2 or -OH:
  • a compound according to any one of 1 to 61 , wherein -R 12 ⁇ 1 if present, is independently N-OH. 65. A compound according to any one of 1 to 64, wherein -R 12 "*, if present, is independently -CH 2 -NH 2 .
  • each of Q 2 , Q 6 and Q 8 is independently C or N;
  • -R 01 is independently cyclopropyl, saturated aliphatic phenyl, pyridinyl, and is optionally substituted, or (a) together with -R Q8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C- M sheterocycle and is optionally substituted, or (b) together with -R 02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C ⁇ eheterocycle and is optionally substituted; and wherein:
  • -R 02 if present, and if Q 2 is C, is independently -H or together with -R Q1 and the atoms to which they are connected forms a saturated or unsaturated alicyclic C ⁇ heterocycle and is optionally substituted;
  • -R Q5 if present, is independently -H, -Me, or -NH 2 ;
  • -R Q6 if present, and if Q 6 is C, is independently -H or -F, or together with -R Q7 , if present, and the atoms to which they are attached forms a saturated or unsaturated alicyclic C ⁇ heterocycle, and is optionally substituted;
  • -R Q8 if present, and if Q 8 is C, is independently -H, -F, -Cl, -OMe,
  • 94 A compound according to any one of 1 to 88, wherein -R 01 , if present, independently (b) together with -R 02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C ⁇ heterocycle and is optionally substituted.
  • -X- if present, is independently -X 1 -, -X 2 - or -X 3 -
  • -X 1 - is independently cyclopropylene, and is optionally substituted
  • -X 2 - is independently saturated aliphatic C 2 alkylene and is optionally substituted
  • -X 3 - is independently C 6 arylene, and is optionally substituted
  • -R 07 is independently -R Q7A , -R Q7B , or -R Q7C , or together with -R Q6 and the atoms to which they are attached forms a saturated or unsaturated alicyclic C ⁇ heterocycle, and is optionally substituted;
  • -R Q7A if present, is independently C ⁇ aryl, and is optionally substituted;
  • -R Q7B is independently saturated alicyclic Cs-ioheterocyclyl, and is optionally substituted;
  • -R Q7C is independently -H or -Me
  • R S2 is independently selected from:
  • -R Q1 is optionally substituted with one or more substituents, -R 53 , wherein each R 53 , if present, is independently selected from:
  • each of -R Q2 -, if present, -R Q6 -, if present, -R Q7 -, if present, and -R Q8 -, if present, is optionally substituted with one or more substituents, -R 34 , wherein each R 54 , if present, is independently selected from:
  • each R 35 is independently selected from:
  • -R Q7A - is optionally substituted with one or more substituents, -R S6 , wherein each -R S6 , if present, is independently selected from:
  • R Q7A - is optionally substituted with one or more substituents, -R S7 , wherein each R S7 , if present, is independently selected from:
  • each -R SS1 is independently saturated aliphatic d- ⁇ alkyl
  • each -L SS1 - is independently -(CH 2 J n -, wherein n is independently 1 to 4.
  • each R S1 is independently selected from:
  • each R S1 if present, is independently -R SS1 .
  • each R S2 is independently selected from:
  • each R S2 is independently selected from:
  • each -R SS1 if present, is independently saturated aliphatic Ci- 3 alkyl.
  • a pharmaceutical composition comprising a compound according to any one of 1 to 151 , and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method of preparing a pharmaceutical composition comprising admixing a compound according to any one of 1 to 151 , and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method of killing bacteria in a host, in vitro or in vivo comprising contacting the host with an effective amount of a compound according to any one of 1 to 151.
  • a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of 1 to 151.
  • a compound according to 159, wherein the treatment comprises treatment with both (i) a compound according to any one of 1 to 151 and (ii) one or more other antibacterial agents.
  • a compound according to 159 or 160, wherein the treatment is treatment of a disease or condition that is mediated or caused by bacteria.
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compound is selected from BP-4Q-001, BP-4Q-002, BP- 4Q-003, BP-4Q-004, BP-4Q-005, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
  • the compound is selected from BP-4Q-001 , BP-4Q-002, BP- 4Q-003, BP-4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
  • the compound is selected from BP-4Q-001 , BP-4Q-002, BP-
  • the compound is selected from BP-4Q-001 , BP-4Q-002, BP- 4Q-004, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP- 4Q-012.
  • the compound is selected from BP-4Q-001 , BP-4Q-002, BP- 4Q-007, BP-4Q-008 and BP-4Q-009.
  • the compound is selected from BP-4Q-001 , BP-4Q-002, BP- 4Q-007, BP-4Q-008 and BP-4Q-009.
  • the compound is independently BP-4Q-001 , BP-4Q-002, BP- 4Q-007 and BP-4Q-009. In embodiments, the compound is selected from BP-4Q-002 and BP-4Q-007.
  • One aspect of the present invention pertains to BP-4Q compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form.
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds.
  • the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer.
  • the substantially purified form refers to a mixture of enantiomers.
  • the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate).
  • the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1 % by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; - and -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-fomns; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • Ci- 7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • keto-, enol-, and enolate-forms as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • keto enol enolate as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 FV, NHR 3 + , NR 4 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CHa) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybe ⁇ zoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • a reference to a particular compound also includes salt forms thereof.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO- R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide
  • a carboxylic acid group may be protected as an ester for example, as: an Ci- 7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci- 7 haloalkyl ester (e.g., a Ci- 7 trihaloalkyl ester); a triCi -7 alkylsilyl-Ci- 7 alkyl ester; or a Cs- ⁇ oaryl-Cwalkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an Ci- 7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a Ci- 7 haloalkyl ester e.g., a Ci- 7 trihaloalkyl ester
  • prodrug refers to a compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.)-
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • the following scheme shows the general method for synthesising BP-4Q compounds of the present invention, comprising the steps of forming a "linker"-substituted benzyl pyrimidine and then coupling with a chloro-substituted quinolone to form the linked BP-4Q compound.
  • the method involves the following steps:
  • Step I synthesis of ⁇ /-benzylaminoalcohols
  • Step II synthesis of 4-(2-(4-benzylpiperazin-1-yl)ethoxy)-3,5-dimethoxybenzaldehyde
  • Step III synthesis of 5-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)-3,5-dimethoxybenzyl)- pyrimidine-2,4-diamine;
  • Step IV synthesis of 5-(4-(2-(piperazin-1-yl)ethoxy)-3,5-dimethoxybenzyl)pyrimidine-
  • Step V synthesis of 7-(4-(2-(4-((2,4-diaminopyrimidin-5-yl)methyl)-2,6- dimethoxyphenoxy)ethyl)piperazin-1 -yl)-1 -cyclopropyl-6-fluoro-i ,4-dihydro-4-oxo-1 ,8- naphthyridine-3-carboxylic acid.
  • the linker in the BP-4Q compound can be changed.
  • the fluoroquinolone can be changed in step V to provide a different 4Q structure in the BP-4Q compound.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a BP-4Q compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing a BP-4Q compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of microbe growth or reproduction and/or microbe death.
  • the compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of bacteria growth or reproduction and/or bacteria death.
  • the compounds described herein are useful, for example, in the treatment of infectious diseases and conditions.
  • the compounds described herein are useful, for example, in the treatment of sequelae associated with diseases and conditions that are ameliorated by the inhibition of bacteria growth or reproduction and/or bacteria death.
  • the BP-4Q compounds described herein are for use in a method of (a) inhibiting bacteria growth or reproduction; (b) killing bacteria; or (c) a combination of both of these.
  • the BP-4Q compounds as described herein have a bacteriocidal and/or bacteriostatic activity.
  • Suitable assays for determining antibacterial activity are described herein and/or are known in the art.
  • inhibiting bacteria growth or reproduction is preventing or stopping bacteria growth or reproduction.
  • One aspect of the present invention pertains to a method of inhibiting bacteria growth or reproduction, killing bacteria, or a combination of both of these.
  • the method can be performed in vitro or in vivo. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo.
  • the bacteria is in a host (e.g. a human or animal) and the method includes contacting the host with an effective amount of a BP-4Q compound, as described herein.
  • a host e.g. a human or animal
  • the method includes contacting the host with an effective amount of a BP-4Q compound, as described herein.
  • the method comprises contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
  • One aspect of the present invention pertains to a method of inhibiting bacteria growth or reproduction (e.g., inhibiting binary fission of bacteria cells), comprising contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
  • the method is a method of inhibiting bacteria growth or reproduction in vitro or in vivo, comprising contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
  • One aspect of the present invention pertains to a method of inhibiting bacteria growth or reproduction (e.g., inhibiting binary fission of bacteria cells) in a host, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein. In one embodiment, the method further comprises contacting the host with one or more other antibacterial agents.
  • One aspect of the present invention pertains to a method of killing bacteria, comprising contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
  • the method is a method of killing bacteria in vitro or in vivo, comprising contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
  • One aspect of the present invention pertains to a method of killing bacteria in a host, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein.
  • the method further comprises contacting the host with one or more other antibacterial agents.
  • the BP-4Q compound is provided in the form of a pharmaceutically acceptable composition.
  • Any type of bacteria may be treated, including but not limited to those described herein.
  • a sample of bacteria cells may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed.
  • effect the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient having a bacterial infection or disease of the same type.
  • Another aspect of the present invention pertains to a BP-4Q compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
  • the method of treatment comprises treatment with both (i) a BP- 4Q compound, as described herein, and (ii) one or more other antibacterial agents.
  • Another aspect of the present invention pertains to use of a BP-4Q compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the BP-4Q compound.
  • the treatment comprises treatment with both (i) a medicament comprising a BP-4Q compound, as described herein, and (ii) one or more other antibacterial agents.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a BP-4Q compound, as described herein, preferably in the form of a pharmaceutical composition.
  • the method is a method of treatment of a bacterial infection or disease.
  • the method further comprises administering to the subject one or more other antibacterial agents.
  • the BP-4Q compounds of the present invention can be used to treat any bacterial infection or disease.
  • the BP-4Q compounds of the present invention can be used to reduce or prevent growth or reproduction of an infecting bacterium and/or kill an infecting bacterium.
  • infecting bacterium is meant a bacterium that has established infection in the host, and which may be associated with a disease or undesirable symptom as a result.
  • infecting bacteria of interest are pathogenic bacteria, and may include a culture of multiple bacteria which together act to cause the pathology. Treatment may require elimination of a single, or multiple types of bacteria.
  • pathogenic bacteria bacteria that causes, or is capable of causing disease. Pathogenic bacteria propagate on or in tissues and may obtain nutrients and other essential materials from their hosts. As used herein, the term “pathogenicity”, “pathogenic” and the like refers to a capability of causing disease and/or degree of capacity to cause disease to its host. The term is applied to parasitic micro-organisms in relation to their hosts.
  • Pathogenic bacteria are a major cause of human death and disease and cause infections such as tetanus, typhoid fever, diphtheria, syphilis, cholera, foodborne illness, leprosy and tuberculosis. Bacterial diseases are also important in agriculture, with bacteria causing leaf spot, fire blight and wilts in plants, as well as Johne's disease, mastitis, salmonella and anthrax in farm animals.
  • drug-resistant bacteria or “antibiotic-resistant bacteria” is meant a bacterial strain that is resistant to growth inhibition or killing by an antibiotic. Multi-drug resistant bacteria are resistant to two or more antibiotics classes. Drug resistance can encompass, for example, ineffective killing of the infecting bacteria such that at least an infectious dose remains in the subject and the infection continues, resulting in continued symptoms of the associated infectious disease or later evidence of such symptoms. Drug resistance can also encompass inhibiting growth of the drug- resistant bacteria until such time therapy is discontinued, after which the bacteria begin to replicate and further the infectious disease.
  • inhibiting bacterial growth or reproduction in the context of infection of an incapacitated bacterial cell according to the invention is meant that, following infection of the bacteria, the bacterial host cell's normal transcriptional and/or translational mechanisms are compromised such that the infected bacteria does not undergo substantial cell division (replication by binary fission) and is caused to enter a state of bacteriostasis. The stasis causes pathogenic effects to also regress.
  • infectious disease or "infectious disorder” is meant a disease arising from the presence of a microbial agent, particularly a bacteria, in a host.
  • the microbial agent may be an infectious bacteria or an infectious fungi, which gives rise to a bacterial infectious disease or a fungal infectious disease, respectively.
  • BP-4Q compounds as described herein can be used to treat diseases or conditions arising from infection of a host with one or more species of bacteria.
  • treatment is treatment of any one of the diseases, disorders or conditions described herein.
  • the activity of the BP-4Q compounds as described herein may be a bacteriocidal or bacteriostatic activity, or both.
  • the anti-bacterial effect may arise through one or more mechanisms.
  • the compounds of the present invention may be used in the treatment of the bacterial diseases described herein, independent of the mechanism.
  • treatment refers generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis
  • treatment is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment.”
  • treatment includes the prophylaxis of bacterial infection, reducing the incidence of bacterial infection, alleviating the symptoms of bacterial infection, etc.
  • terapéuticaally-effective amount refers to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, other antibacterial compounds.
  • a compound as described herein may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1 , 2, 3, 4) agents or therapies that regulates bacteria growth or reproduction and/or bacteria survival.
  • one or more other agents or therapies that regulates bacteria growth or reproduction and/or bacteria survival.
  • several characteristic features of bacterial infection may be treated.
  • One aspect of the present invention pertains to a BP-4Q compound as described herein, in combination with one or more additional therapeutic agents.
  • agents i.e., the compound described here, plus one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • BP-4Q compounds described herein may also be used as cell culture additives to inhibit bacteria growth or reproduction.
  • BP-4Q compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • BP-4Q compounds described herein may also be used as a standard, for example, in an assay, in order to identify other antibacterial compounds, etc.
  • kits comprising (a) a BP-4Q compound as described herein, or a composition comprising a BP-4Q compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the kit further comprises one or more other antibacterial agents.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the BP-4Q compound or pharmaceutical composition comprising the BP-4Q compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action). Oral administration is an example.
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird (e.g.
  • canine e.g., a dog
  • feline e.g., a cat
  • equine e.g., a horse
  • porcine e.g., a pig
  • ovine e.g., a sheep
  • bovine e.g., a cow
  • a primate simian (e.g., a monkey or ape)
  • a monkey e.g., marmoset, baboon
  • an ape e.g., gorilla, chimpanzee, orangutang, gibbon
  • a human e.g., gorilla, chimpanzee, orangutang, gibbon
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • the subject/patient is not a human.
  • BP-4Q compound While it is possible for the BP-4Q compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one BP-4Q compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one BP-4Q compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients. 5th edition. 2005.
  • Step III Synthesis of 5-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)-3.5-dimethoxybenzyl)- D yrimidine-2.4-diamine:
  • Step IV Synthesis of 5-(4-(2-(piperazin-1-yl)ethoxy)-3.5- dimethoxybenzyl)oyrimidine-2.4-diamine:
  • Step V Synthesis of 7-(4-(2-(4-((2.4-diaminopyrimidin-5-yl)methyl)-2.6- dimethoxyphenoxy)ethyl)piperazin-1 -yl)- 1 -cyclopropyl- ⁇ -fluoro- 1.4-dihydro-4-oxo- 1.8-naohth yridine-3-carboxylic acid.
  • Method A Gradient elution using 25-100% acetonitrile-water with 0.1% formic acid in 7.5min, 1.5mL/min, Xterra ® column MSC18, 2.5micron, 4.6x20mm using Agilent 1100 analytical hplc system.
  • Method B Gradient elution using 0-40-100% acetonitrile-water with 0.1% formic acid (0-40% in 5 min, 40-100% in 2.5min), 1.5mlJmin, Xterra ® column MSC18, 2.5micron, 4.6x20mm using Agilent 1100 analytical hplc system.
  • MICs Minimum inhibitory concentrations
  • Bacterial strains were prepared by colony suspension to an optical density equivalent to a 0.5 McFarland Standard, and then diluted in cation-adjusted Mueller-Hinton broth (CAMHB) that had been supplemented with 0.0022% Tween-80. 90 ⁇ l of this inoculum was added to each test well. The final concentration of cells was 5.5 x 10 s CFU/mL.
  • CAMHB cation-adjusted Mueller-Hinton broth
  • S. aureus 29213 and E. coli 25922 are sensitive to ciprofloxacin (CIP) and TMP and were obtained from the American Type Culture Collection (ATCC), Manassus, VA, USA.
  • S. aureus NRS19 is sensitive to TMP but resistant to CIP.
  • S. epidermidis NRS60 is sensitive to CIP but resistant to TMP.
  • S. aureus NRS119 is resistant to both CIP and TMP.
  • Biological data were obtained using the antibacterial assays described above for the following compounds: BP-4Q-001 through BP-4Q-012 as well as for CIP, TMP and an equimolar mixture of CIP/TMP.
  • the following compounds had a minimum inhibitory concentration of less than 10 ⁇ g/ml: BP-4Q-001 , BP-4Q-002, BP-4Q-003, BP-
  • the following compounds had a minimum inhibitory concentration of less than 5 ⁇ g/ml: BP-4Q-002, BP-4Q-003, BP-4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
  • the following compounds had a minimum inhibitory concentration of 1 ⁇ g/ml or less: BP-4Q-001, BP-4Q-002, BP-4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
  • CIP had a minimum inhibitory concentration of 0.5 ⁇ g/ml.
  • TMP had a minimum inhibitory concentration of 2 ⁇ g/ml.
  • the equimolar mixture of CIP/TMP had a minimum inhibitory concentration of 0.5 ⁇ g/ml.
  • the following compounds had a minimum inhibitory concentration of less than 10 ⁇ g/ml: BP-4Q-001 , BP-4Q-002, BP-4Q-003, BP- 4Q-004, BP-4Q-005, BP-4Q-007, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP- 4Q-012.
  • the following compounds had a minimum inhibitory concentration of less than 5 ⁇ g/ml: BP-4Q-002, BP-4Q-003, BP-4Q-004, BP-4Q-005, BP-4Q-007, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
  • CIP had a minimum inhibitory concentration of 0.0078 ⁇ M.
  • TMP had a minimum inhibitory concentration of 1 ⁇ g/ml.
  • the equimolar mixture of CIP/TMP had a minimum inhibitory concentration of ⁇ 0.125 ⁇ M.
  • the following compounds had a minimum inhibitory concentration of less than 20 ⁇ g/ml: BP-4Q-001, BP-4Q-002, BP-4Q-003, BP- 4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
  • aureus NRS19 assay the following compounds had a minimum inhibitory concentration of less than 10 ⁇ g/ml: BP-4Q-001 , BP-4Q-002, BP-4Q-004, BP- 4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP- 4Q-012.
  • the following compounds had a minimum inhibitory concentration of less than 5 ⁇ g/ml: BP-4Q-002, BP-4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
  • CIP had a minimum inhibitory concentration of 32 ⁇ g/ml M.
  • TMP had a minimum inhibitory concentration of 4 ⁇ g/ml.
  • the equimolar mixture of CIP/TMP had a minimum inhibitory concentration of 8 ⁇ g/ml.
  • the following compounds had a minimum inhibitory concentration of less than 5 ⁇ g/ml: BP-4Q-001 , BP-4Q-002, BP-4Q-004, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.

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Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain antimicrobial compounds comprising pharmacophores based on or comprising benzyl pyrimidines and 4-quinolones or 4H-4-oxoquinolizines (for convenience, collectively referred to herein as "BP-4Q compounds"), which, inter alia, are antimicrobial, particularly antibacterial. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to provide an antimicrobial function, particularly an antibacterial function, and in the treatment of diseases and conditions that are mediated by microbes, particularly bacteria, that are ameliorated by the antimicrobial function, particularly an antibacterial function, including bacterial diseases, optionally in combination with another agent, for example, another antibacterial agent.

Description

HYBRID ANTIMICROBIAL COMPOUNDS AND THEIR USE
TECHNICAL FIELD
The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain antimicrobial compounds comprising pharmacophores based on or comprising benzyl pyrimidines and 4-quinolones or 4H-4-oxoquinolizines (for convenience, collectively referred to herein as "BP-4Q compounds"), which, inter alia, are antimicrobial, particularly antibacterial. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to provide an antimicrobial function, particularly an antibacterial function, and in the treatment of diseases and conditions that are mediated by microbes, particularly bacteria, that are ameliorated by the antimicrobial function, particularly an antibacterial function, including bacterial diseases, optionally in combination with another agent, for example, another antibacterial agent.
BACKGROUND
A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like. Ranges are often expressed herein as from "abouf one particular value, and/or to "abouf another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Benzyl pyrimidines and DHFR inhibitors DHFR or Dihydrofolate Reductase is a constitutive enzyme that is specific to bacterial, parasitic and epithelial cells. It reduces dihydrofolate to tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidine acid and certain amino acids. Inhibitors of this enzyme have been used as antibiotics, antimalarial and chemotherapeutic agents. Examples of DHFR inhibitors as antibiotics are Trimethoprim (TMP), brodimoprim, methoprim and etioprim. TMP for example is a widely used antibiotic and is administered orally. It exhibits broad- spectrum antibacterial activity and excellent tolerability. However, bacterial resistance is a problem.
4-Quinolones
Quinolones are a group of broad spectrum antibiotics that act by inhibiting the bacterial DNA gyrase or topoisomerase IV enzyme thereby inhibiting DNA replication and transcription. For many gram negative bacteria DNA gyrase is the target while DNA topoisomerase IV is the target for gram positive bacteria. Eukaryotic cells do not contain DNA gyrase or topoisomerase. The 4-quinolones comprise two types of structures, those with a fluorine atom mainly at C6 (known as Fluoroquinolones, which include the majority of quinolones in clinincal use) and those without. Therapeutically useful quinolones may be divided into two groups, quinolone or 1 , 8- naphthyridone and those with a tricyclic nucleus of the 6, 7 type (oxolinic acid) and of the 1 , 8 type (ofloxacin, levofloxacin.etc). Ciprofloxacin (CIP) is a well known example of a fluoroquinolone. Like TMP it is a widely used orally administered antibiotic with broad-spectrum antibacterial activity but, again like TMP, it also encounters bacterial resistance.
4H-4-Oxoquinolizines
4H-4-oxoquinolizines are a comparatively new addition to the quinolone family, in which nitrogen replaces the carbon between ring carbons C-4 and C-5. They have been used to overcome bacterial resistance to fluoroquinolones. They exhibit antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone- resistant MRSA.
Combination therapies comprising administering two antibiotics have been investigated, for example the combination of TMP and CIP (see, Huovinen et ah, 1992); however the different pharmacokinetic behaviour of the two antibiotics means that there remains a problem of delivering the individual components to the site of infection at the same time and for a sufficient time so that effective treatment can occur.
Hybrid antibiotics comprise two molecules having antibacterial activity linked covalently. Naturally, the covalent linker is important in achieving the desired activity and the mere selection of a second antibacterial as a substituent on a first antibacterial molecule will not guarantee activity (see e.g. WO96/16046). In particular, the hybrid antibacterial approach combines molecules with targets in different bacterial target pathways (e.g. DNA-replication and cell wall biosynthesis, DNA replication and protein biosynthesis) (see e.g. WO2005/070940 and US2006019986). In other words, the primary aim of the hybrid approach has been to overcome resistance by addressing two targets. However, the selection of appropriate antibacterial pharmacophores and linker groups remains a significant hurdle to retaining activity associated with both pharmacophores such that the combined antibacterial action is delivered to the appropriate site. Furthermore, it has not been possible to retain Gram-negative activity even when one of the pharmacophores exhibits Gram-negative activity when used independently. SUMMARY OF THE INVENTION
One aspect of the invention pertains to certain hybrid antibiotic compounds comprising linked benzyl pyrimidines (BP) (e.g. trimethoprim) and 4-quinolones or 4H-4-oxoquinolizines (4Q) (e.g. fluoroquinolone) as described herein.
For convenience, these compounds are collectively referred to herein as "BP-4Q compounds").
Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a BP-4Q compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
Another aspect of the invention pertains to method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing a BP-4Q compounds, as described herein, and a pharmaceutically acceptable carrier or diluent.
Another aspect of the present invention pertains to a method of killing microbes in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein. Thus, the present invention is concerned with providing an antimicrobial action (e.g. an antibacterial and/or antifungal action).
Another aspect of the present invention pertains to a method of inhibiting (e.g. reducing or preventing) growth or reproduction of bacteria, killing bacteria, or a combination of both these, in vitro or in vivo, comprising contacting a host with an effective amount of a BP-4Q compound, as described herein.
In one embodiment, the method further comprises contacting the host with one or more other antibacterial agents.
Another aspect of the present invention pertains to a method of killing bacteria in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein.
In one embodiment, the method further comprises contacting the host with one or more other antibacterial agents. Another aspect of the present invention pertains to a bacteriocidal method using an effective amount of a BP-4Q compound.
Another aspect of the present invention pertains to a method of reducing or preventing the growth or reproduction of bacteria in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein.
Another aspect of the present invention pertains to a bacteriostatic method using an effective amount of a BP-4Q compound.
In one embodiment, the method further comprises contacting the host with one or more other antibacterial agents.
Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a
BP-4Q compound, as described herein, preferably in the form of a pharmaceutical composition.
In one embodiment, the method further comprises administering to the subject one or more other antibacterial agents.
Another aspect of the present invention pertains to a BP-4Q compound as described herein for use in a method of treatment of the human or animal body by therapy.
In one embodiment, the method of treatment comprises treatment with both (i) a BP- 4Q compound as described herein and (ii) one or more other antibacterial agents.
Another aspect of the present invention pertains to use of a BP-4Q compound, as described herein, in the manufacture of a medicament for use in treatment.
In one embodiment, the treatment comprises treatment with both (i) a medicament comprising a BP-4Q compound as described herein and (ii) one or more other antibacterial agents. In one embodiment, the treatment is treatment of a disease or condition that is mediated or caused by bacteria.
In one embodiment, the treatment is treatment of a disease or condition that is ameliorated by the inhibition of bacteria growth or reproduction and/or bacteria death.
In one embodiment, the treatment is treatment of a bacterial infection.
In one embodiment, the treatment is treatment of a bacterial disease.
Another aspect of the present invention pertains to a kit comprising (a) a BP-4Q compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
In one embodiment, the kit further comprises one or more other antibacterial agents.
Another aspect of the present invention pertains to a BP-4Q compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to a BP-4Q compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
Another aspect of the present invention pertains to a method of synthesis of a BP-4Q compound, as described herein. As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Compounds
One aspect of the present invention relates to certain hybrid antibiotic compounds comprising a benzyl pyrimidine linked to a 4-quinolone or 4H-4-oxoquinolizine (for convenience, collectively referred to herein as "BP-4Q compounds"). Benzyl pyrimidines (BP) and 4-quinolones (4Q) are represented below by trimethoprim (TMP) and ciprofloxacin (CIP).
Figure imgf000008_0001
TMP
Figure imgf000008_0002
FQ (ciprofloxacin)
In one embodiment, the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof: NH,
Figure imgf000009_0001
(I)
wherein:
each of -R1 and -R3 is independently -ORA
and wherein:
-R2 is independently -Br or -ORA
wherein:
each -RA is independently saturated aliphatic C1-4 alkyl or -L-A
and wherein at least one of -R1, -R2 and -R3 is -O-L-A
wherein:
-L- is independently -L1 -L2- or -L2-
wherein:
-L1- is independently -L1C- or -L1H-, -L2- is independently -L2H- or -L2*-
wherein: -L1C- is independently saturated aliphatic
Figure imgf000010_0001
alkylene and is optionally substituted,
-L1H- is independently -L1S -L1C-L1Z- or -L1c-L1z-L1c-,
wherein:
-L1Z- is independently -O-, -NRL1Z- or -NC(O)RL1Z-,
wherein:
-RL1Z-, if present, is independently -H, saturated or unsaturated aliphatic Ci-βalkyl, or (λnoaryl, and is optionally substituted,
and wherein:
-L2H- is independently saturated or unsaturated C4-7 heterocyclylene and is optionally substituted,
-L2*- is independently
Figure imgf000010_0002
wherein RL2X, if present, is independently saturated or unsaturated aliphatic d^alkyl and is optionally substituted,
and wherein:
-A is independently a 4-quinolonyl or 4H-4-oxoquinolizinyl. For the avoidance of doubt, a 4-quinolonyl is a monovalent radical formed by removal of a hydrogen atom or other substituent from a 4-quinolone. For further avoidance of doubt, the term "4-quinolone" as used herein includes 1 ,8-naphthyridones.
For the avoidance of doubt, a 4H-4-oxoquinolizinyl is a monovalent radical formed by removal of a hydrogen atom or other substituent from a 4H-4-oxoquinolizine.
For the avoidance of doubt, the indices such as "C4-/ in terms such as "C-wheterocyclylene" refer to the number of ring atoms, whether carbon atoms or heteroatoms. For example, cyclohexylene, piperidinylene, pyridinylene and piperazinylene are example of a Cβcyclylene group.
For the avoidance of doubt, it is not intended that the groups -R1, -R2 and -R3 are linked, other than via the phenyl ring as shown in the above formula.
The Groups -R1 and -R3
Optionally, each of -R1 and -R3 is independently -ORA. Optionally, -R1 is independently -ORA. Optionally, -R3 is independently -ORA.
The Group -R2
Optionally, -R2 is independently -Br or -OR\ Optionally, -R2 is independently -Br. Optionally, -R2 is independently -ORA.
The Group -RA
Optionally, each -RA is independently saturated aliphatic d^alkyl or -L-A. Optionally, each -RA is independently saturated aliphatic Ci-4alkyl. Optionally, each -RA is independently -L-A.
Optionally, each -RA is independently saturated aliphatic Ci-2alkyl. Optionally, each -RA is -Me.
The Group -L-
Optionally, -L- is independently -L1-L2- or -L2-. Optionally, -L- is independently -L1-L2-. Optionally, -L- is independently -L2-.
The Group -L1-
Optionally, -L1-, if present, is independently -L1C- or -L1H-. Optionally, -L1-, if present, is independently -L1C-. Optionally, -L1-, if present, is independently -L1H-.
The Group — L1C-
Optionally, -L1C-, if present, is independently saturated or unsaturated aliphatic Ci-4 alkylene and is optionally substituted.
Optionally, -L1 c-, if present, is independently saturated aliphatic Ci-4alkylene and is optionally substituted.
Optionally, -L1 c-, if present, is independently saturated aliphatic d^alkylene and is optionally substituted.
Optionally, -L1 c-, if present, is independently saturated aliphatic Ci-2alkylene and is optionally substituted.
Optionally, -L1 c-, if present, is independently saturated aliphatic C2alkylene and is optionally substituted.
Optionally, -L1 C-, if present, is independently aliphatic Cialkylene and is optionally substituted. Optionally, -L1C-, if present, is independently -CH2-, -CH2-CH2-, -CH(CH3)-CH2-, - CH2-C(CHa)2- or -CH2-CH2-CH2-. Optionally, -L1C-, if present, is independently -CH2-. Optionally, -L1C-, if present, is independently -CH2-CH2-. Optionally, -L1C-, if present, is independently -CH(CH3)-CH2. Optionally, -L1S if present, is independently -CH2-C(CH3)2-. Optionally, -L1C-, if present, is independently -CH2-CH2-CH2-.
The Group -L1H-
Optionally, -L1H-, if present, is independently -L1Z- , -L1C-L1Z- or -L1C-L1Z-L1C-.
Optionally, -L1H-, if present, is independently -L1Z-.
Optionally, -L1H-, if present, is independently -L1C-L1Z-.
Optionally, -L1H-, if present, is independently -L1C-L1Z-L1C-.
The Group -L1Z-
Optionally, -L1Z-, if present, is independently -O-, -NRL1Z- or -NC(O) RL1Z-. Optionally, -L1Z-, if present, is independently -O-. Optionally, -L1Z-, if present, is independently -NRL1Z-.
Optionally, -L1Z-, if present, is independently -NC(O)RL1Z-.
The Group -RL1Z-
Optionally, -RL1Z-, if present, is independently -H, saturated or unsaturated aliphatic Ci-6alkyl, or C4-ioaryl, and is optionally substituted.
Optionally, -RL1Z-, if present, is independently -H.
Optionally, -RL1Z-, if present, is independently saturated or unsaturated aliphatic Ci-
6alkyl, and is optionally substituted.
Optionally, -RL1Z-, if present, is independently C-noaryl, and is optionally substituted.
Optionally, -RL1Z-, if present, is independently saturated aliphatic d^alkyl, and is optionally substituted.
Optionally, -RL1Z-, if present, is independently C6aryl, and is optionally substituted. The Group -L2-
Optionally, -L2-, if present, is independently -L2H- or L2*-. Optionally, -L2-, if present, is independently -L2H-. Optionally, -L2-, if present, is independently -L2*-.
The Group -L2H-
Optionally, -L2H-, if present, is independently saturated or unsaturated C4- 7heterocyclylene and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated or unsaturated C4. βheterocyclylene and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated or unsaturated C5. βheterocyclylene and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated alicyclic C4heterocyclylene and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated alicyclic Csheterocyclylene and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated alicyclic C6heterocyclylene and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated or unsaturated C4. βheterocyclylene wherein one or more ring atoms are N, and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated or unsaturated C4. βheterocyclylene wherein one ring atom is N, and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated or unsaturated C4. sheterocyclylene wherein one ring atom is N, and is optionally substituted. Optionally, -L2H-, if present, is independently saturated or unsaturated C5- βheterocyclylene wherein one ring atom is N, and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated alicyclic C4heterocyclylene wherein one ring atom is N, and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated alicyclic Csheterocyclylene wherein one ring atom is N, and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated alicyclic Cβheterocyclylene wherein one ring atom is N, and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated or unsaturated C4- βheterocyclylene wherein two ring atoms are N, and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated or unsaturated Cβheterocyclylene wherein two ring atoms are N, and is optionally substituted.
Optionally, -L2H-, if present, is independently saturated alicyclic Cβheterocyclylene wherein two ring atoms are N, and is optionally substituted.
Optionally, -L2H-, if present, is independently a divalent group derived from azetidine, pyrrolidine, piperidine or piperazine, and is optionally substituted.
Optionally, -L2H-, if present, is independently azetidinylene , pyrrolidinylene , piperidinylene , or piperazinylene , and is optionally substituted.
Optionally, -L2H-, if present, is independently azetidinylene, and is optionally substituted. Optionally, -L2H-, if present, is independently pyrrolidinylene, and is optionally substituted.
Optionally, -L2H-, if present, is independently piperidinylene, and is optionally substituted.
Optionally, -L2H-, if present, is independently piperazinylene, and is optionally substituted. Optionally, -L2H-, if present, is independently bonded through a heteroatom of the heterocyclylene.
Optionally, -L2H-, if present, is independently bonded through two heteroatoms of the heterocyclylene.
Optionally, -L2H-, if present, is independently selected from the following, wherein, if present, -FP™ is independently -CH2-NH2, -OH or =N-OH and R2LHB is independently -CH2-NH2 or -OH:
Figure imgf000016_0001
RL2HB ι-K>-'
The Group -R12"*
Optionally, if present, -R1-2"* is independently -CH2-NH2, -OH or =N-OH.
Optionally, if present, -R1-2^ is independently -CH2-NH2.
Optionally, if present, -R1-2^ is independently -OH.
Optionally, if present, -R12"* is independently =N-OH.
The Group -R1-2"8
Optionally, if present, -R12"* is independently -CH2-NH2 or -OH. Optionally, if present, -R12"* is independently -CH2-NH2. Optionally, if present, -R12"* is independently -OH.
The Group -L2*-
Optionally, -L2*-, if present, is independently
Figure imgf000017_0001
wherein RL2X, if present, is independently saturated or unsaturated aliphatic and is optionally substituted.
The Group FPX
Optionally, -RL2X-1 if present, is saturated or unsaturated aliphatic C1-4 alkyl and is optionally substituted.
Optionally, -R1-2*-, if present, is saturated aliphatic d.2 alkyl and is optionally substituted.
Optionally, -R12*-, if present, is Ci alkyl and is optionally substituted. Optionally, -R12*-, if present, is -CH2-NH2.
The Group -A
Optionally, -A is independently 4-quinolonyl or 4H-4-oxoquinolizinyl. Optionally, -A is independently 4-quinolonyl. Optionally, -A is independently 4H-4-oxoquinolizinyl.
Optionally, -A is independently 4-quinolon-7-yl or 4H-4-oxoquinolizin-8-yl.
Optionally, -A is independently fluoro-4-quinolonyl. Optionally, -A is independently 6-fluoro-4-quinolonyl.
Optionally, -A is independently fluoro-4H-4-oxoquinolizinyl. Optionally, -A is independently 7-fluoro-4H-4-oxoquinolizinyl.
Optionally, -A is independently -A1 or -A2. Optionally, -A is independently -A1. Optionally, -A is independently -A2.
The Group -A1 Optionally, -A1, if present, is independently
Figure imgf000018_0001
wherein:
each of Q2, Q6 and Q8 is independently C or N;
and wherein:
-RQ1 is independently cyclopropyl, saturated aliphatic d^alkyl, phenyl, pyridinyl, and is optionally substituted, or (a) together with -RQ8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^eheterocycle and is optionally substituted, or (b) together with -RQ2 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C4-6heterocycle and is optionally substituted;
and wherein:
-RQ2, if present, and if Q2 is C, is independently -H or together with -RQ1 and the atoms to which they are connected forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted;
and wherein:
-RQ5, if present, is independently -H, -Me, or -NH2;
and wherein:
-R06, if present, and if Q6 is C, is independently -H or -F, or together with -R07, if present, and the atoms to which they are attached forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted;
and wherein:
-RQ8, if present, and if Q8 is C, is independently -H, -F, -Cl, -OMe, -OCH2F, -OCHF2, -OCF3, -CF3, -CN or together with -RQ1 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted
The Groups Q2. Q6 and Q8
Optionally, each of Q2, Q6 and Q8 is independently C or N. Optionally, Q2 is independently C or N. Optionally, Q6 is independently C or N. Optionally, Q8 is independently C or N.
Optionally, Q2 is independently C. Optionally, Q2 is independently N.
Optionally, Q6 is independently C. Optionally, Q6 is independently N.
Optionally, Q8 is independently C. Optionally, Q8 is independently N.
The Group - RQ1
Optionally, -RQ1 is independently cyclopropyl, saturated aliphatic Chalky!, phenyl, pyridinyl, and is optionally substituted, or (a) together with -RQ8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic
Figure imgf000019_0001
and is optionally substituted, or (b) together with -R02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted.
Optionally, -RQ1 is independently cyclopropyl, and is optionally substituted.
Optionally, -RQ1 is independently saturated aliphatic d^alkyl and is optionally substituted.
Optionally, -RQ1 is independently phenyl and is optionally substituted.
Optionally, -RQ1 is independently pyridinyl, and is optionally substituted.
Optionally, -RQ1 independently (a) together with -RQ8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C4-6heterocycle and is optionally substituted.
Optionally, -RQ1 independently (b) together with -R02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted.
Optionally, -RQ1 is independently cyclopropyl, -CH2-CH3, -CH2-CH2F, or difluorophenyl.
The Group - RQ2
Optionally, -R°2, if present, and if Q2 is C, is independently -H or together with -R01 and the atoms to which they are attached forms a saturated or unsaturated alicyclic C4heterocycle and is optionally substituted.
Optionally, -RQ2, if present, and if Q2 is C, is independently -H.
Optionally, -RQ2, if present, and if Q2 is C, independently together with -RQ1 and the atoms to which they are connected forms a saturated alicyclic C4heterocycle and is optionally substituted. Optionally, -RQ2, if present, and if Q2 is C, independently together with -RQ1 and the atoms to which they are connected forms:
Figure imgf000021_0001
The Group - RQ5
Optionally, -RQ5, if present, is independently -H, -Me, or -NH2. Optionally, -R05, if present, is independently -H. Optionally, -RQ5, if present, is independently -Me. Optionally, -RQS, if present, is independently -NH2.
The Group -RQ6
Optionally, -R06, if present, and if Q6 is C, is independently -H or -F, or together with
-RQ7 and the atoms to which they are attached forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted.
Optionally, -RQ6, if present, and if Qβ is C, is independently -F.
Optionally, -RQ6, if present, and if Q6 is C, is independently -H. Optionally, -RQ6, if present, and if Q6 is C, independently together with -R07 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C4- βheterocycle, and is optionally substituted.
Optionally, -RQ6, if present, and if Q6 is C, independently together with -RQ7 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic Csheterocycle, and is optionally substituted.
Optionally, -RQ6, if present, and if Q6 is C, independently together with -RQ7 and the atoms to which they are attached, forms:
Figure imgf000022_0001
The Group -R08
Optionally, -RQ8, if present, and if Q8 is C, is independently -H, -F, -Cl, -OMe, -
OCH2F, -OCHF2, -OCF3, -CF3, -CN or together with -RQ1 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted. Optionally, -R08, if present, and if Q8 is C, is independently -H.
Optionally, -R08, if present, and if Q8 is C, is independently -F.
Optionally, -RQ8, if present, and if Q8 is C, is independently -Cl.
Optionally, -R08, if present, and if Q8 is C, is independently -OMe.
Optionally, -RQ8, if present, and if Q8 is C, is independently -OCH2F. Optionally, -RQ8, if present, and if Q8 is C, is independently -OCHF2.
Optionally, -RQ8, if present, and if Q8 is C, is independently -OCF3.
Optionally, -RQ8, if present, and if Q8 is C, is independently -CF3.
Optionally, -R08, if present, and if Q8 is C, is independently -CN.
Optionally, -RQ8, if present, and if Q8 is C, independently together with -RQ1 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C4. eheterocycle and is optionally substituted.
The Group -A2
Optionally, -A2, if present, is independently
Figure imgf000022_0002
wherein:
-X-, if present, is independently -X1-, -X2- or -X3-
wherein:
-X1-, if present, is independently cyclopropylene, and is optionally substituted
and wherein:
-X2-, if present, is independently saturated aliphatic C2alkylene and is optionally substituted
and wherein:
-X3-, if present, is independently C6arylene, and is optionally substituted
and wherein:
-R07, if present, is independently -RQ7A, -RQ7B, or -RQ7C, or together with -RQ6 and the atoms to which they are attached forms a saturated or unsaturated alicyclic
Figure imgf000023_0001
and is optionally substituted;
wherein:
-RQ7A, if present, is independently C6aryl, and is optionally substituted;
and wherein: -RQ7B, if present, is independently saturated alicyclic Cs-ioheterocyclyl, and is optionally substituted;
and wherein:
-RQ7C, if present, is independently -H or -Me;
The Group -X-
Optionally, -X-, if present, is independently -X1-, -X2- or -X3-.
Optionally, -X-, if present, is independently -X1-.
Optionally, -X-, if present, is independently -X2-.
Optionally, -X-, if present, is independently -X3-.
The Group -X1-
Optionally, -X1-, if present, is independently cyclopropylene, and is optionally substituted. Optionally, -X1-, if present, is independently
Figure imgf000024_0001
The Group -X2-
Optionally, -X2-, if present, is independently saturated aliphatic C2alkylene and is optionally substituted. Optionally, -X2-, if present, is independently -CH2-CH2-.
The Group -X3-
Optionally ,.-X3-, if present, is independently Cβarylene, and is optionally substituted. Optionally ,.-X3-, if present, is independently phenylene, and is optionally substituted. The Group -RQ7
Optionally, -R07, if present, is independently -RQ7A, -RQ7B, or -RQ7C, or together with - R06 and the atoms to which they are attached forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted. Optionally, -R07, if present, is independently -RQ7A. Optionally, -RQ7, if present, is independently -RQ7B. Optionally, -R07, if present, is independently -RQ7C. Optionally, -R07, if present, independently together with -RQ6 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted.
Optionally, -RQ7, if present, independently together with -RQ6 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C5heterocycle, and is optionally substituted.
Optionally, -RQ7, if present, independently together with -RQ6 and the atoms to which they are attached, forms:
Figure imgf000025_0001
The Group -RQ7A
Optionally, -RQ7A, if present, is independently C6aryl, and is optionally substituted.
Optionally, -RQ7A, if present, is independently phenyl, and is optionally substituted.
Optionally, -RQ7A, if present, is independently
Figure imgf000025_0002
The Group -RQ7B
Optionally, -RQ7B, if present, is independently saturated or unsaturated alicyclic Cs- toheterocyclyl, and is optionally substituted.
Optionally, -RQ7B, if present, is independently saturated or unsaturated alicyclic C5- βheterocyclyl, and is optionally substituted.
Optionally, -RQ7B, if present, is independently piperidino, piperazino or pyrrolidino, and is optionally substituted.
The Group -RQ7C
Optionally, -RQ7C, if present, is independently -H or -Me.
Optional Substituents on RA and R12*
In one embodiment, RA is optionally substituted with one or more substituents, -RS1.
In one embodiment, RL2X is optionally substituted with one or more substituents, -RS1.
In one embodiment, each RS1, if present, is independently selected from:
-F, -Cl, -Br, -I,
-CF3, -OCF3, -SCF3,
-OH, -LSS1-OH, -O-LSS1-OH, -NH-LSS1-OH, -NRSS1-LSS1-OH,
-ORSS1,
-NH2, -NHRss1, -NRssl 2, or -LSS1-NH2, -LSS1-NHRSS1, -LSS1-NRSS1 2
In one embodiment, each RS1, if present, is independently selected from:
-F, -Cl, -Br, -I, or -NH2 In one embodiment, each RS1, if present, is independently selected from -R531.
Optional Substituents on -L2H-
In one embodiment, -L2H- is optionally substituted with one or more substituents, -RS2.
In one embodiment, each RS2, if present, is independently selected from:
-RSS1,
-F, -Cl, -Br, -I1
-CF3, -OCF3, -SCF3,
-OH, -LSS1-OH, -O-LSS1-OH, -NH-LSS1-OH, -NRSS1-LSS1-OH,
-ORSS1, -LSS1-ORSS1, -O-LSS1-ORSS1, -NH-LSS1-ORSS1, -NRSS1-LSS1-ORSS1, -SH, -SRSS1,
-CN,
-NH2, -NHRSS1, -NRSS12,
-LSS1-NH2, -LSS1-NHRSS1, -LSS1-NRSS1 2, or
=N-OH.
In one embodiment, each RS2, if present, is independently selected from:
-F, -Cl, -Br, -I1 -CF3, -OCF3, -SCF3,
-OH, -LSS1-OH, -O-LSS1-OH, -NH-LSS1-OH, -NRSS1-LSS1-OH,
-NH2, -NHRSS1, -NRSS1 2,
-LSS1-NH2, -LSS1-NHRSS1, -LSS1-NRSS1 2, or
=N-OH.
In one embodiment, each RS2, if present, is independently selected from:
-RSS1,
-OH, -LSS1-OH, -NH2, -NHRSS\ -NRSS1 2, -L^-NH2, -L∞'-NHR881, -LSS1-NRSS1 2, or =N-OH.
In one embodiment, each RS2, if present, is independently selected from:
-OH1
=N-OH.
Optional Substituents on -RQ1
In one embodiment, -RQ1 is optionally substituted with one or more substituents, -R33.
In one embodiment, each RS3, if present, is independently selected from:
-F, -Cl, -Br, -I, or -OH
Optional Substituents on -R02. -RQ6. -RQ7 and -R08.
In one embodiment, -RQ2- is optionally substituted with one or more substituents, - R34.
In one embodiment, -RQ6- is optionally substituted with one or more substituents, - R34.
In one embodiment, -RQ7- is optionally substituted with one or more substituents, - R34.
In one embodiment, -RQ8- is optionally substituted with one or more substituents, - R34.
In one embodiment, each R34, if present, is independently selected from: -F, -Cl, -Br, -I1 or -OH
Optional Substituents on -X3-.
In one embodiment, -X3- is optionally substituted with one or more substituents, -RS5.
In one embodiment, each RS5, if present, is independently selected from:
-F, -Cl, -Br, -I, or -OH
Optional Substituents on -RQ7A-.
In one embodiment, -RQ7A- is optionally substituted with one or more substituents, - R36.
In one embodiment, each -R36, if present, is independently selected from:
-F, -Cl, -Br, -I, two adjacent groups -RS6, if present, together form -CH2-NH-C(Me)H-
Optional Substituents on -RQ7B-.
In one embodiment, -RQ7A- is optionally substituted with one or more substituents, - RS7.
In one embodiment, each RS7, if present, is independently selected from:
-Me, -OH, -NHMe, -NH2, -CH2NH2, =N-OMe, -CH2-CH2-, two adjacent groups -RS7, if present, together form -CH2-CH2-CH2-NH-, two adjacent groups -RS7, if present, together form -CH(NH2)-, or
Figure imgf000030_0001
Elements of the Optional Substituents. -RS1 . -RS2. -R53. -R34. -RS5. -RS6 and -RS7
Optionally, each -RSS1, if present, is independently saturated aliphatic Ci-βalkyl.
Optionally, each -RSS1, if present, is independently saturated aliphatic Ci-3alkyl.
Optionally, each -RSS1, if present, is independently -Me.
Optionally, each -LSS1-, if present, is independently -(CH2Jn-, wherein n is independently 1 to 4.
Optionally, each -LSS1-, if present, is independently -CH2- or -CH2CH2-.
Embodiments
The BP-4Q compounds as described herein combine two pharmacophores, both of which share a single target area (DNA synthesis), but each addresses independent individual steps in that target area. This novel approach of targeting different steps in the same target system may provide a synergistic effect in terms of efficacy. In addition, combining the two pharmacophores in the hybrid molecule suitably addresses some or all of the difficulties associated with the different pharmacokinetic behaviour of the two antibiotics such that the individual components can be delivered to the site of infection at the same time and for a sufficient time so that effective treatment can occur. Furthermore, suitably the benefits of the overall approach include one or more of low resistance selection propensity, activity against strains with resistance against one of the pharmacophores, and reduced susceptibility to efflux pump mechanism. Another advantage could be that the toxicity of either or both of the component antibiotics is reduced in the combined hybrid antibiotic.
In embodiments, -R2 is -O-L-A.
In embodiments, -L- is -U-L2- or -L2-; -L1-, if present, is -L1H- and -L2- is -L2H-.
In embodiments, -L- is independently selected from:
Figure imgf000031_0001
In embodiments, -L- is independently
Figure imgf000031_0002
In embodiments, -L- is independently
Figure imgf000032_0001
In embodiments, -L- is -L2- and -L2- is -L2"-.
In embodiments, -L2X- is independently
Figure imgf000032_0002
In embodiments, -L- is -L1-L2-, -L1- is -L1C- and -L2- is -L2N-.
In embodiments, -L- is -L1-L2- and -L1- is -L1C-.
In embodiments, -L1C- is independently -CH2-, -CH2-CH2-, -CH(CH3)-CH2-, -CH2- C(CH3J2- or -CH2-CH2-CH2-.
In embodiments, -L1C- is independently -CH2-, -CH2-CH2-, -CH(CH3)-CH2-, -CH2- C(CHs)2- or -CH2-CH2-CH2- and -L2- is -L2H-.
In embodiments, -L1C- is independently -CH2-, -CH2-CH2-, -CH(CH3)-CH2-, -CH2- C(CH3);.- or -CH2-CH2-CH2-; -L2- is -L2H-; and -L2H- is independently saturated or unsaturated C4^ heterocyclylene wherein one or more ring atoms are N, and is optionally substituted.
In embodiments, -L- is -L1-L2-; -L1- is -L1C-L1Z-L1C-; and -L1C-L1Z-L1C- is independently -CH2-CH2-O-CH2-CH2-.
In embodiments, -A is -A1.
In embodiments, -A1 is independently selected from:
Figure imgf000033_0001
In embodiments, -A is -A2.
In embodiments, -A2 is independently selected from:
Figure imgf000033_0002
Aspects and embodiments of the invention are set out in the following numbered paragraphs: 1. A compound of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
NH,
Figure imgf000034_0001
(D
wherein:
each of -R1 and -R3 is independently -OR'
and wherein:
-R2 is independently -Br or -ORΛ
wherein:
-RA is independently saturated aliphatic C1-4 alkyl or -L-A;
and wherein at least one of -R1, -R2 and -R3 is -O-L-A
wherein:
-L- is independently -L1 -L2- or -L2-
wherein:
-L1- is independently -L1C- or -L1H-, -L2- is independently -L2H- or -L2*- wherein:
-L1C- is independently saturated aliphatic C1-4 alkylene and is optionally substituted,
-L1H- is independently -L1Z-, -L1C-UZ- or -L1C-L1Z-L1C-,
wherein:
-L1Z- is independently -O-, -NRL1Z- or
-NC(O)RL1Z-,
wherein:
-RL1Z-, if present, is independently -H, saturated or unsaturated aliphatic Ci-βalkyl, or C-noaryl, and is optionally substituted,
and wherein:
-L2H- is independently saturated or unsaturated C4-? heterocyclylene and is optionally substituted,
-L2*- is independently
Figure imgf000035_0001
wherein RL2X, if present, is independently saturated or unsaturated aliphatic d.4alkyl and is optionally substituted,
and wherein: -A is independently a 4-quinolonyl or 4H-4-oxoquinolizinyl.
2. A compound according to 1 , wherein -R2 is independently -Br.
3. A compound according to 1 or 2, wherein -R2 is independently -ORΛ
4. A compound according to any one of 1 to 3, wherein -RA is independently saturated aliphatic d^alkyl.
5. A compound according to any one of 1 to 3, wherein -RA is independently saturated aliphatic Ci-4alkyl.
6. A compound according to any one of 1 to 3, wherein -RA is independently saturated aliphatic d-2alkyl.
7. A compound according to any one of 1 to 3, wherein -RA is independently - Me.
8. A compound according to any one of 1 to 3, wherein -RA is independently -L- A.
9. A compound according to any one of 1 to 8, wherein -L- is independently -L1- L2-.
10. A compound according to any one of 1 to 8, wherein -L- is independently -L2- 11. A compound according to any one of 1 to 10, wherein -L1-, if present, is independently -L1C-.
12. A compound according to any one of 1 to 10, wherein -L1-, if present, is independently -L1H-.
13. A compound according to any one of 1 to 12, wherein -L1C-, if present, is independently saturated or unsaturated aliphatic Ci-4 alkylene and is optionally substituted.
14. A compound according to any one of 1 to 12, wherein -L1 c-, if present, is independently saturated aliphatic Ci-4alkylene and is optionally substituted.
15. A compound according to any one of 1 to 12, wherein -L1 c-, if present, is independently saturated aliphatic d^alkylene and is optionally substituted.
16. A compound according to any one of 1 to 12, wherein -L1 c-, if present, is independently saturated aliphatic Ci-2alkylene and is optionally substituted.
17. A compound according to any one of 1 to 12, wherein -L1 C-, if present, is independently saturated aliphatic C2alkylene and is optionally substituted.
18. A compound according to any one of 1 to 12, wherein -L1 C-, if present, is independently aliphatic Cialkylene and is optionally substituted.
19. A compound according to any one of 1 to 12, wherein -L1C-, if present, is independently -CH2-, -CH2-CH2-, -CH(CHa)-CH2-, -CH2-C(CHs)2- or -CH2-CH2-CH2-
20. A compound according to any one of 1 to 12, wherein -L1C-, if present, is independently -CH2-.
21. A compound according to any one of 1 to 12, wherein -L1C-, if present, is independently -CH2-CH2-. 22. A compound according to any one of 1 to 12, wherein -L1C-, if present, is independently -CH(CH3)-CH2.
23. A compound according to any one of 1 to 12, wherein -L1C-, if present, is independently -CH2-C(CHa)2-.
24. A compound according to any one of 1 to 12, wherein -L1C-, if present, is independently -CH2-CH2-CH2-.
25. A compound according to any one of 1 to 24, wherein -L1H-, if present, is independently -L1Z-.
26. A compound according to any one of 1 to 24, wherein -L1H-, if present, is independently -L1C-L1Z-.
27. A compound according to any one of 1 to 24, wherein -L1H-, if present, is independently -L1C-L1Z-L1C-.
28. A compound according to any one of 1 to 27, wherein -L1Z-, if present, is independently -O-.
29. A compound according to any one of 1 to 27, wherein -L1Z-, if present, is independently -NRL1Z-.
30. A compound according to any one of 1 to 27, wherein -L1Z-, if present, is independently -NC(O)RL1Z-. 31. A compound according to any one of 1 to 30, wherein -RL1Z-, if present, is independently-H.
32. A compound according to any one of 1 to 30, wherein -RL1Z-, if present, is independently saturated or unsaturated aliphatic Chalky I, and is optionally substituted.
33. A compound according to any one of 1 to 30, wherein -RL1Z-, if present, is independently C-noaryl, and is optionally substituted.
34. A compound according to any one of 1 to 30, wherein -RL1Z-, if present, is independently saturated aliphatic d^alkyl, and is optionally substituted.
35. A compound according to any one of 1 to 30, wherein -RL1Z-, if present, is independently C6aryl, and is optionally substituted.
36. A compound according to any one of 1 to 35, wherein -L2-, if present, is independently -L2H-.
37. A compound according to any one of 1 to 35, wherein -L2-, if present, is independently -L2*-.
38. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated or unsaturated C^heterocyclylene and is optionally substituted.
39. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated or unsaturated C^heterocyclylene and is optionally substituted. 40. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated alicyclic C4heterocyclylene and is optionally substituted.
41. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated alicyclic Csheterocyclylene and is optionally substituted.
42. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated alicyclic Cβheterocyclylene and is optionally substituted.
43. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated or unsaturated Csheterocyclylene wherein one or more ring atoms are N, and is optionally substituted.
44. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated or unsaturated Csheterocyclylene wherein one ring atom is N, and is optionally substituted.
45. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated or unsaturated Csheterocyclylene wherein one ring atom is N, and is optionally substituted.
46. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated or unsaturated Cs-eheterocyclylene wherein one ring atom is N, and is optionally substituted.
47. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated alicyclic C4heterocyclylene wherein one ring atom is N, and is optionally substituted.
48. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated alicyclic Csheterocyclylene wherein one ring atom is N, and is optionally substituted. 49. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated alicyclic Cβheterocyclylene wherein one ring atom is N, and is optionally substituted.
50. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated or unsaturated C^heterocyclylene wherein two ring atoms are N, and is optionally substituted.
51. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated or unsaturated Cβheterocyclylene wherein two ring atoms are N, and is optionally substituted.
52. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently saturated alicyclic Cβheterocyclylene wherein two ring atoms are N, and is optionally substituted.
53. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently a divalent group derived from azetidine, pyrrolidine, piperidine or piperazine, and is optionally substituted.
54. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently azetidinylene , pyrrolidinylene , piperidinylene , or piperazinylene , and is optionally substituted.
55. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently azetidinylene, and is optionally substituted.
56. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently pyrrolidinylene, and is optionally substituted.
57. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently piperidinylene, and is optionally substituted.
58. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently piperazinylene, and is optionally substituted. 59. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently bonded through a heteroatom of the heterocyclylene.
60. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently bonded through two heteroatoms of the heterocyclylene.
61. A compound according to any one of 1 to 37, wherein -L2H-, if present, is independently selected from the following, wherein, if present, -R12"* is independently -CH2-NH2, -OH or =N-OH and R2LHB is independently -CH2-NH2 or -OH:
Figure imgf000042_0001
62. A compound according to any one of 1 to 61 , wherein -R12^1 if present, is independently -CH2-NH2.
63. A compound according to any one of 1 to 61 , wherein -R128*, if present, is independently -OH.
64. A compound according to any one of 1 to 61 , wherein -R12^1 if present, is independently =N-OH. 65. A compound according to any one of 1 to 64, wherein -R12"*, if present, is independently -CH2-NH2.
66. A compound according to any one of 1 to 64, wherein -FP"*, if present, is independently -OH.
67. A compound according to any one of 1 to 66, wherein -Ft12'*-, if present, is saturated aliphatic Cv2 alkyl and is optionally substituted.
68. A compound according to any one of 1 to 66, wherein -FP*-, if present, is Ci alkyl and is optionally substituted.
69. A compound according to any one of 1 to 66, wherein -Ft1-2*-, if present, is - CH2-NH2.
70. A compound according to any one of 1 to 69, wherein -A is independently 4- quinolonyl.
71. A compound according to any one of 1 to 69, wherein -A is independently 4H- 4-oxoquinolizinyl.
72. A compound according to any one of 1 to 69, wherein -A is independently 4- quinolon-7-yl or 4H-4-oxoquinolizin-8-yl.
73. A compound according to any one of 1 to 69 and 72, wherein -A is independently fluoro-4-quinolonyl.
74. A compound according to 73, wherein -A is independently 6-fluoro-4- quinolonyl. 75. A compound according to any one of 1 to 69 and 72, wherein -A is independently fluoro-4H-4-oxoquinolizinyl.
76. A compound according to 75, wherein -A is independently 7-fluoro-4H-4- oxoquinolizinyl.
77. A compound according to any one of 1 to 69, wherein -A is independently -A1 or -A2.
78. A compound according to any one of 1 to 77, wherein -A is independently A1.
79. A compound according to any one of 1 to 78, wherein -A1, if present, is independently
Figure imgf000044_0001
wherein:
each of Q2, Q6 and Q8 is independently C or N;
and wherein:
-R01 is independently cyclopropyl, saturated aliphatic
Figure imgf000044_0002
phenyl, pyridinyl, and is optionally substituted, or (a) together with -RQ8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C-Msheterocycle and is optionally substituted, or (b) together with -R02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^eheterocycle and is optionally substituted; and wherein:
-R02, if present, and if Q2 is C, is independently -H or together with -RQ1 and the atoms to which they are connected forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted;
and wherein:
-RQ5, if present, is independently -H, -Me, or -NH2;
and wherein:
-RQ6, if present, and if Q6 is C, is independently -H or -F, or together with -RQ7 , if present, and the atoms to which they are attached forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted;
and wherein:
-RQ8, if present, and if Q8 is C, is independently -H, -F, -Cl, -OMe,
-OCH2F, -OCHF2, -OCF3, -CF3, -CN or together with -RQ1 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C4- eheterocycle, and is optionally substituted
80. A compound according to any one of 1 to 79, wherein Q2, if present, is independently C or N.
81. A compound according to any one of 1 to 80, wherein Q6, if present, is independently C or N.
82. A compound according to any one of 1 to 81 , wherein Q8, if present, is independently C or N. 83. A compound according to any one of 1 to 82, wherein Q2, if present, is independently C.
84. A compound according to any one of 1 to 82, wherein Q2, if present, is independently N.
85. A compound according to any one of 1 to 84, wherein Q8, if present, is independently C.
86. A compound according to any one of 1 to 84, wherein Q6, if present, is independently N.
87. A compound according to any one of 1 to 86, wherein Q8, if present, is independently C.
88. A compound according to any one of 1 to 86, wherein Q8, if present, is independently N.
89. A compound according to any one of 1 to 88, wherein, -RQ1, if present, is independently cyclopropyl, and is optionally substituted.
90. A compound according to any one of 1 to 88, wherein -RQ1, if present, is independently saturated aliphatic d^alkyl and is optionally substituted.
91. A compound according to any one of 1 to 88, wherein -RQ1, if present, is independently phenyl and is optionally substituted.
92. A compound according to any one of 1 to 88, wherein -RQ1, if present, is independently pyridinyl, and is optionally substituted.
93. A compound according to any one of 1 to 88, wherein -RQ1, if present, independently (a) together with -R08 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted. 94. A compound according to any one of 1 to 88, wherein -R01, if present, independently (b) together with -R02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted.
95. A compound according to any one of 1 to 88, wherein -RQ1, if present, is independently cyclopropyl, -CH2-CH3, -CH2-CH2F, or difluorophenyl.
96. A compound according to any one of 1 to 95, wherein -RQ2, if present, and if Q2 is C, is independently -H.
97. A compound according to any one of 1 to 95, wherein -RQ2, if present, and if Q2 is C, independently together with -RQ1 and the atoms to which they are connected forms a saturated alicyclic C4heterocycle and is optionally substituted.
98. A compound according to any one of 1 to 95, wherein -RQ2, if present, and if Q2 is C, independently together with -RQ1 and the atoms to which they are connected forms:
99. A compound according to any one of 1 to 98, wherein -R05, if present, is independently -H.
100. A compound according to any one of 1 to 98, wherein -R05, if present, is independently -Me. 101. A compound according to any one of 1 to 98, wherein -RQ5, if present, is independently -NH2.
102. A compound according to any one of 1 to 101 , wherein -RQβ, if present, and if Q6 is C, is independently -H.
103. A compound according to any one of 1 to 101 , wherein -RQ6, if present, and if Q6 is C, is independently -F.
104. A compound according to any one of 1 to 101 , wherein -RQ6, if present, and if Q6 is C, independently together with -R07 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted.
105. A compound according to any one of 1 to 101 , wherein -RQ6, if present, and if Q6 is C, independently together with -R07 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic Csheterocycle, and is optionally substituted.
106. A compound according to any one of 1 to 101 , wherein -RQ6, if present, and if Q6 is C, independently together with -RQ7 and the atoms to which they are attached, forms:
Figure imgf000048_0001
107. A compound according to any one of 1 to 106, wherein -R08, if present, and if Q8 is C, is independently -H. 108. A compound according to any one of 1 to 106, wherein -R08, if present, and if Q8 is C, is independently -F.
109. A compound according to any one of 1 to 106, wherein -RQ8, if present, and if Q8 is C, is independently -Cl.
110. A compound according to any one of 1 to 106, wherein -RQ8, if present, and if Q8 is C, is independently -OMe.
1 1 1. A compound according to any one of 1 to 106, wherein -R08, if present, and if Q8 is C, is independently -OCH2F.
112. A compound according to any one of 1 to 106, wherein -RQ8, if present, and if Q8 is C, is independently -OCHF2.
113. A compound according to any one of 1 to 106, wherein -RQ8, if present, and if Q8 is C, is independently -OCF3.
1 14. A compound according to any one of 1 to 106, wherein -RQ8, if present, and if Q8 is C, is independently -CF3.
115. A compound according to any one of 1 to 106, wherein -RQ8, if present, and if Q8 is C, is independently -CN.
116. A compound according to any one of 1 to 106, wherein -R08, if present, and if Q8 is C, independently together with -RQ1 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C-Msheterocycle and is optionally substituted.
117. A compound according to any one of 1 to 77, wherein -A is independently - A2. 118. A compound according to any one of 1 to 117, wherein -A2, if present, is independently
Figure imgf000050_0001
wherein:
-X-, if present, is independently -X1-, -X2- or -X3-
wherein:
-X1-, if present, is independently cyclopropylene, and is optionally substituted
and wherein:
-X2-, if present, is independently saturated aliphatic C2alkylene and is optionally substituted
and wherein:
-X3-, if present, is independently C6arylene, and is optionally substituted
and wherein:
-R07, if present, is independently -RQ7A, -RQ7B, or -RQ7C, or together with -RQ6 and the atoms to which they are attached forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted; wherein:
-RQ7A, if present, is independently Cβaryl, and is optionally substituted;
and wherein:
-RQ7B, if present, is independently saturated alicyclic Cs-ioheterocyclyl, and is optionally substituted;
and wherein:
-RQ7C, if present, is independently -H or -Me;
1 19. A compound according to any one of 1 to 1 17, wherein -X-, if present, is independently -X1-.
120. A compound according to any one of 1 to 1 17, wherein -X-, if present, is independently -X2-.
121. A compound according to any one of 1 to 1 17, wherein -X-, if present, is independently -X3-.
122. A compound according to any one of 1 to 121 , wherein -X1-, if present, is independently
Figure imgf000051_0001
\ 123. A compound according to any one of 1 to 121 , wherein -X2-, if present, is independently -CH2-CH2-.
124. A compound according to any one of 1 to 121 , wherein -X3-, if present, is independently phenylene, and is optionally substituted.
125. A compound according to any one of 1 to 124, wherein -R07, if present, is independently -RQ7A.
126. A compound according to any one of 1 to 124, wherein -R07, if present, is independently -RQ7B.
127. A compound according to any one of 1 to 124, wherein -R07, if present, is independently -RQ7C.
128. A compound according to any one of 1 to 124, wherein -RQ7, if present, independently together with -RQ6 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C4-6heterocycle, and is optionally substituted.
129. A compound according to any one of 1 to 124, wherein -R°7, if present, independently together with -RQβ and the atoms to which they are attached, forms a saturated or unsaturated alicyclic Csheterocycle, and is optionally substituted.
130. A compound according to any one of 1 to 124, wherein -RQ7, if present, independently together with -RQ6 and the atoms to which they are attached, forms:
Figure imgf000052_0001
131. A compound according to any one of 1 to 130, wherein -RQ7A, if present, is independently C6aryl, and is optionally substituted.
132. A compound according to any one of 1 to 130, wherein -RQ7A, if present, is independently phenyl, and is optionally substituted.
133. A compound according to any one of 1 to 130, wherein -RQ7A, if present, is independently
Figure imgf000053_0001
134. A compound according to any one of 1 to 130, wherein -RQ7B, if present, is independently saturated or unsaturated alicyclic Cs-ioheterocyclyl, and is optionally substituted.
135. A compound according to any one of 1 to 130, wherein -R07B, if present, is independently saturated or unsaturated alicyclic Cs-eheterocyclyl, and is optionally substituted.
136. A compound according to any one of 1 to 130, wherein -RQ7B, if present, is independently piperidino, piperazino or pyrrolidino, and is optionally substituted.
137. A compound according to any one of 1 to 130, wherein -RQ7C, if present, is independently -H or -Me. 138. A compound according to any one of 1 to 137, wherein each of RA and R12*, if present, is optionally substituted with one or more substituents, -Rs\ wherein each RS1 is independently selected from:
-F, -Cl, -Br, -I, -CF31 -OCF31 -SCF3,
-OH, -LSS1-OH, -O-LSS1-OH, -NH-LSS1-OH, -NRSS1-LSS1-OH, -ORSS1,
-NH2, -NHRSS1, -NRSS1 2, or -LSS1-NH2, -LSS1-NHRSS1, -LSS1-NRSS1 2
and wherein -L2H-, if present, is optionally substituted with one or more substituents, - RS2, wherein each RS2 is independently selected from:
-F, -Cl, -Br, -I,
-CF3, -OCF3, -SCF3,
-OH, -LSS1-OH, -O-LSS1-OH, -NH-LSS1-OH, -NRSS1-LSS1-OH,
-ORSSi 1 .LSSL0RSSi 1 -O-LSS1-ORSS1, -NH-LSS1-ORSS1, -NRSS1-LSS1-ORSS1,
-SH, -SRSS1, -CN,
-NH2, -NHRSS1, -NRSS1 2,
-LSS1-NH2, -LSS1-NHRSS1, -LSS1-NRSS1 2, or
=N-OH.
and wherein -RQ1 is optionally substituted with one or more substituents, -R53, wherein each R53, if present, is independently selected from:
-F, -Cl, -Br, -I1 or -OH
and wherein each of -RQ2-, if present, -RQ6-, if present, -RQ7-, if present, and -RQ8-, if present, is optionally substituted with one or more substituents, -R34, wherein each R54, if present, is independently selected from:
-F, -Cl, -Br, -I, or -OH
and wherein -X3-, if present, is optionally substituted with one or more substituents, - RS5, wherein each R35 is independently selected from:
-RSS1,
-F, -Cl, -Br, -I, or -OH
and wherein -RQ7A-, if present, is optionally substituted with one or more substituents, -RS6, wherein each -RS6, if present, is independently selected from:
-F, -Cl, -Br, -I, two adjacent groups -RS6, if present, together form -CH2-NH-C(Me)H-
and wherein -RQ7A-, if present, is optionally substituted with one or more substituents, -RS7, wherein each RS7, if present, is independently selected from:
-Me, -OH,
-NHMe,
-NH2,
-CH2NH2,
=N-OMe, -CH2-CH2-, two adjacent groups -RS7, if present, together form -CH2-CI-I2-CH2-NH-, two adjacent groups -RS7, if present, together form -CH(NH2)-, or
Figure imgf000056_0001
wherein:
each -RSS1, if present, is independently saturated aliphatic d-βalkyl; and
each -LSS1-, if present, is independently -(CH2Jn-, wherein n is independently 1 to 4.
139. A compound according to 138, wherein each RS1, if present, is independently selected from:
-RSS1
-F, -Cl, -Br, -I, or -NH2
140. A compound according to 138, wherein each RS1, if present, is independently -RSS1.
141. A compound according to any one of 138 to 140, wherein each RS2, if present, is independently selected from:
-RSS1,
-F, -Cl, -Br, -I,
-CF3, -OCF3, -SCF3,
-OH, -LSS1-OH, -O-LSS1-OH, -NH-LSS1-OH, -NRSS1-LSS1-OH,
-NH2, -NHRSS1, -NRSS1 2, -LSS1-NH2, -LSS1-NHRSS1, -LSS1-NRSS1 2, or
=N-OH. 142. A compound according to any one of 138 to 141 , wherein each RS2, if present, is independently selected from:
-Rss\
-OH, -LSS1-OH, -NH2, -NHFV531, -NRSS12, -LSS1-NH2, -LSS1-NHRSS1, -LSS1-NRSS1 2, or =N-OH.
143. A compound according to any one of 138 to 142, wherein each RS2, if present, is independently selected from:
-OH, -LSS1-NH2, or
=N-OH.
144. A compound according to any one of 138 to 143, wherein each R33, if present, is independently selected from:
-F, -Cl, -Br, -I, or -OH
145. A compound according to any one of 138 to 144, wherein each -RSS1, if present, is independently saturated aliphatic Ci-3alkyl.
146. A compound according to any one of 138 to 145, wherein each -RSS1, if present, is independently -Me.
147. A compound according to any one of 138 to 146, wherein each -LSS1-, if present, is independently -(CH2),,-, wherein n is independently 1 to 4. 148. A compound according to any one of 138 to 147, wherein each -LSS1-, if present, is independently -CH2- or -CH2CH2-.
149. A compound according to any one of 1 to 148, wherein -L- is independently selected from:
Figure imgf000058_0001
150. A compound according to any one of 1 to 149, wherein -A is independently selected from:
Figure imgf000059_0001
151. A compound according to any one of 1 to 150, wherein the compound is selected from BP-4Q-001 , BP-4Q-002, BP-4Q-003, BP-4Q-004, BP-4Q-005, BP- 4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP- 4Q-012.
152. A pharmaceutical composition comprising a compound according to any one of 1 to 151 , and a pharmaceutically acceptable carrier, diluent, or excipient.
153. A method of preparing a pharmaceutical composition comprising admixing a compound according to any one of 1 to 151 , and a pharmaceutically acceptable carrier, diluent, or excipient.
154. A method of killing microbes in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a compound according to any one of 1 to 151. 155. A method of inhibiting growth or reproduction of bacteria, killing bacteria, or a combination of both these, in vitro or in vivo, comprising contacting a host with an effective amount of a compound according to any one of 1 to 151.
156. A method of killing bacteria in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a compound according to any one of 1 to 151.
157. A method of reducing or preventing the growth or reproduction of bacteria in a host, in vitro or in vivo, comprising contacting the host with an effective amount of a compound according to any one of 1 to 151.
158. A method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of 1 to 151.
159. A compound according to any one of 1 to 151 for use in a method of treatment of the human or animal body by therapy.
160. A compound according to 159, wherein the treatment comprises treatment with both (i) a compound according to any one of 1 to 151 and (ii) one or more other antibacterial agents.
161. A compound according to 159 or 160, wherein the treatment is treatment of a disease or condition that is mediated or caused by bacteria.
162. A compound according to any one of 159 to 161 , wherein the treatment is treatment of a disease or condition that is ameliorated by the inhibition of bacteria growth or reproduction and/or bacteria death.
163. A compound according to any one of 159 to 162, wherein the treatment is treatment of a bacterial infection. 164. A compound according to any one of 159 to 162, wherein the treatment is treatment of a bacterial disease.
165. Use of a compound according to any one of 1 to 151 in the manufacture of a medicament for use in treatment.
166. A method of synthesis of a compound according to any one of 1 to 151.
Combinations
Each and every compatible combination of the optional features, embodiments (including those defined with reference to numbered paragraphs) described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.
Specific Embodiments
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
In embodiments, the compound is selected from BP-4Q-001, BP-4Q-002, BP- 4Q-003, BP-4Q-004, BP-4Q-005, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
In embodiments, the compound is selected from BP-4Q-001 , BP-4Q-002, BP- 4Q-003, BP-4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
In embodiments, the compound is selected from BP-4Q-001 , BP-4Q-002, BP-
4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
In embodiments, the compound is selected from BP-4Q-001 , BP-4Q-002, BP- 4Q-004, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP- 4Q-012.
In embodiments, the compound is selected from BP-4Q-001 , BP-4Q-002, BP- 4Q-007, BP-4Q-008 and BP-4Q-009.
In embodiments, the compound is selected from BP-4Q-001 , BP-4Q-002, BP- 4Q-007, BP-4Q-008 and BP-4Q-009.
In embodiments, the compound is independently BP-4Q-001 , BP-4Q-002, BP- 4Q-007 and BP-4Q-009. In embodiments, the compound is selected from BP-4Q-002 and BP-4Q-007.
Substantially Purified Forms
One aspect of the present invention pertains to BP-4Q compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
Unless specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1 % by weight.
Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer. In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
Isomers
Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; - and -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-fomns; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers
(i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
Figure imgf000066_0001
keto enol enolate
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; and the like.
Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
Salts
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL Vol. 66, pp. 1-19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO ), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2FV, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CHa)4 +.
If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH3 +), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybeπzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.
Solvates and Hydrates
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof. Chemically Protected Forms
It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc).
For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (-NRCO- R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide
(-NHCO-OC(CH3J2C6H4C6Hs, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH- Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O ).
For example, a carboxylic acid group may be protected as an ester for example, as: an Ci-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci-7haloalkyl ester (e.g., a Ci-7trihaloalkyl ester); a triCi-7alkylsilyl-Ci-7alkyl ester; or a Cs-ϋoaryl-Cwalkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).
Prodrugs
It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.)- For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Chemical Synthesis
Methods for the chemical synthesis of BP-4Q compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
The following scheme shows the general method for synthesising BP-4Q compounds of the present invention, comprising the steps of forming a "linker"-substituted benzyl pyrimidine and then coupling with a chloro-substituted quinolone to form the linked BP-4Q compound.
HO 850C
Figure imgf000071_0001
NMP
Figure imgf000071_0002
Figure imgf000071_0003
The method involves the following steps:
Step I: synthesis of Λ/-benzylaminoalcohols;
Step II: synthesis of 4-(2-(4-benzylpiperazin-1-yl)ethoxy)-3,5-dimethoxybenzaldehyde
Step III: synthesis of 5-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)-3,5-dimethoxybenzyl)- pyrimidine-2,4-diamine;
Step IV: synthesis of 5-(4-(2-(piperazin-1-yl)ethoxy)-3,5-dimethoxybenzyl)pyrimidine-
2,4-diamine; and
Step V: synthesis of 7-(4-(2-(4-((2,4-diaminopyrimidin-5-yl)methyl)-2,6- dimethoxyphenoxy)ethyl)piperazin-1 -yl)-1 -cyclopropyl-6-fluoro-i ,4-dihydro-4-oxo-1 ,8- naphthyridine-3-carboxylic acid.
By selecting appropriate linker group precursors in place of the 2-(4-benzylpiperazin- 1-yl)ethanol shown in the scheme, the linker in the BP-4Q compound can be changed. Similarly, the fluoroquinolone can be changed in step V to provide a different 4Q structure in the BP-4Q compound. Compositions
One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising a BP-4Q compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a BP-4Q compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
Uses
The compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of microbe growth or reproduction and/or microbe death.
The compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of bacteria growth or reproduction and/or bacteria death.
The compounds described herein are useful, for example, in the treatment of infectious diseases and conditions.
The compounds described herein are useful, for example, in the treatment of sequelae associated with diseases and conditions that are ameliorated by the inhibition of bacteria growth or reproduction and/or bacteria death.
Use in Methods of Killing Bacteria or Inhibiting Bacteria Growth or Reproduction
The BP-4Q compounds described herein are for use in a method of (a) inhibiting bacteria growth or reproduction; (b) killing bacteria; or (c) a combination of both of these. Thus, the BP-4Q compounds as described herein have a bacteriocidal and/or bacteriostatic activity.
Suitable assays for determining antibacterial activity (e.g. bacteriostatic or bacteriocidal activity) are described herein and/or are known in the art.
Suitably, inhibiting bacteria growth or reproduction is preventing or stopping bacteria growth or reproduction.
One aspect of the present invention pertains to a method of inhibiting bacteria growth or reproduction, killing bacteria, or a combination of both of these.
The method can be performed in vitro or in vivo. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo.
In one embodiment, the bacteria is in a host (e.g. a human or animal) and the method includes contacting the host with an effective amount of a BP-4Q compound, as described herein.
Suitably the method comprises contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
One aspect of the present invention pertains to a method of inhibiting bacteria growth or reproduction (e.g., inhibiting binary fission of bacteria cells), comprising contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
In one embodiment, the method is a method of inhibiting bacteria growth or reproduction in vitro or in vivo, comprising contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
One aspect of the present invention pertains to a method of inhibiting bacteria growth or reproduction (e.g., inhibiting binary fission of bacteria cells) in a host, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein. In one embodiment, the method further comprises contacting the host with one or more other antibacterial agents.
One aspect of the present invention pertains to a method of killing bacteria, comprising contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
In one embodiment, the method is a method of killing bacteria in vitro or in vivo, comprising contacting the bacteria with an effective amount of a BP-4Q compound, as described herein.
One aspect of the present invention pertains to a method of killing bacteria in a host, comprising contacting the host with an effective amount of a BP-4Q compound, as described herein.
In one embodiment, the method further comprises contacting the host with one or more other antibacterial agents.
In one embodiment, the BP-4Q compound is provided in the form of a pharmaceutically acceptable composition.
Any type of bacteria may be treated, including but not limited to those described herein.
One of ordinary skill in the art is readily able to determine whether or not a candidate compound possesses bacteriocidal and/or bacteriostatic activity. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein.
For example, a sample of bacteria cells may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient having a bacterial infection or disease of the same type.
Use in Methods of Therapy
Another aspect of the present invention pertains to a BP-4Q compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
In one embodiment, the method of treatment comprises treatment with both (i) a BP- 4Q compound, as described herein, and (ii) one or more other antibacterial agents.
Use in the Manufacture of Medicaments
Another aspect of the present invention pertains to use of a BP-4Q compound, as described herein, in the manufacture of a medicament for use in treatment.
In one embodiment, the medicament comprises the BP-4Q compound.
In one embodiment, the treatment comprises treatment with both (i) a medicament comprising a BP-4Q compound, as described herein, and (ii) one or more other antibacterial agents.
Methods of Treatment
Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a BP-4Q compound, as described herein, preferably in the form of a pharmaceutical composition. In one embodiment, the method is a method of treatment of a bacterial infection or disease.
In one embodiment, the method further comprises administering to the subject one or more other antibacterial agents.
Conditions Treated - Bacterial Infections and Bacterial Diseases The BP-4Q compounds of the present invention can be used to treat any bacterial infection or disease. In particular, the BP-4Q compounds of the present invention can be used to reduce or prevent growth or reproduction of an infecting bacterium and/or kill an infecting bacterium.
By "infecting bacterium" is meant a bacterium that has established infection in the host, and which may be associated with a disease or undesirable symptom as a result. Generally, infecting bacteria of interest are pathogenic bacteria, and may include a culture of multiple bacteria which together act to cause the pathology. Treatment may require elimination of a single, or multiple types of bacteria.
By "pathogenic bacteria" is meant bacteria that causes, or is capable of causing disease. Pathogenic bacteria propagate on or in tissues and may obtain nutrients and other essential materials from their hosts. As used herein, the term "pathogenicity", "pathogenic" and the like refers to a capability of causing disease and/or degree of capacity to cause disease to its host. The term is applied to parasitic micro-organisms in relation to their hosts.
Pathogenic bacteria are a major cause of human death and disease and cause infections such as tetanus, typhoid fever, diphtheria, syphilis, cholera, foodborne illness, leprosy and tuberculosis. Bacterial diseases are also important in agriculture, with bacteria causing leaf spot, fire blight and wilts in plants, as well as Johne's disease, mastitis, salmonella and anthrax in farm animals.
By "drug-resistant bacteria" or "antibiotic-resistant bacteria" is meant a bacterial strain that is resistant to growth inhibition or killing by an antibiotic. Multi-drug resistant bacteria are resistant to two or more antibiotics classes. Drug resistance can encompass, for example, ineffective killing of the infecting bacteria such that at least an infectious dose remains in the subject and the infection continues, resulting in continued symptoms of the associated infectious disease or later evidence of such symptoms. Drug resistance can also encompass inhibiting growth of the drug- resistant bacteria until such time therapy is discontinued, after which the bacteria begin to replicate and further the infectious disease. By "inhibition of bacterial growth or reproduction" in the context of infection of an incapacitated bacterial cell according to the invention is meant that, following infection of the bacteria, the bacterial host cell's normal transcriptional and/or translational mechanisms are compromised such that the infected bacteria does not undergo substantial cell division (replication by binary fission) and is caused to enter a state of bacteriostasis. The stasis causes pathogenic effects to also regress.
By "infectious disease" or "infectious disorder" is meant a disease arising from the presence of a microbial agent, particularly a bacteria, in a host. The microbial agent may be an infectious bacteria or an infectious fungi, which gives rise to a bacterial infectious disease or a fungal infectious disease, respectively.
Types of Disease/ Disorder
BP-4Q compounds as described herein can be used to treat diseases or conditions arising from infection of a host with one or more species of bacteria.
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), treatment is treatment of any one of the diseases, disorders or conditions described herein.
The activity of the BP-4Q compounds as described herein may be a bacteriocidal or bacteriostatic activity, or both.
The anti-bacterial effect may arise through one or more mechanisms. The compounds of the present invention may be used in the treatment of the bacterial diseases described herein, independent of the mechanism.
Treatment
The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment."
For example, treatment includes the prophylaxis of bacterial infection, reducing the incidence of bacterial infection, alleviating the symptoms of bacterial infection, etc.
The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
Combination Therapies
The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, other antibacterial compounds.
For example, it may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1 , 2, 3, 4) agents or therapies that regulates bacteria growth or reproduction and/or bacteria survival. In this way, several characteristic features of bacterial infection may be treated.
One aspect of the present invention pertains to a BP-4Q compound as described herein, in combination with one or more additional therapeutic agents.
The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use. Other Uses
The BP-4Q compounds described herein may also be used as cell culture additives to inhibit bacteria growth or reproduction.
The BP-4Q compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
The BP-4Q compounds described herein may also be used as a standard, for example, in an assay, in order to identify other antibacterial compounds, etc.
Kits
One aspect of the invention pertains to a kit comprising (a) a BP-4Q compound as described herein, or a composition comprising a BP-4Q compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
In one embodiment, the kit further comprises one or more other antibacterial agents.
The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
Routes of Administration
The BP-4Q compound or pharmaceutical composition comprising the BP-4Q compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action). Oral administration is an example. The Subiect/Patient
The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird (e.g. a chicken)), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.
In one preferred embodiment, the subject/patient is a human.
In another embodiment, the subject/patient is not a human.
Formulations
While it is possible for the BP-4Q compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one BP-4Q compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one BP-4Q compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients. 5th edition. 2005.
EXAMPLES
The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
Chemical Synthesis
With reference to the general scheme given above, the following compounds were synthesised.
Step I: Synthesis of N-benzylaminoalcohols
Step 1a:
HO-7
Figure imgf000081_0001
To a solution of the 2-(piperazin-1-yl)ethanol (1.0 mmol) in 5 mL anhydrous THF was added benzyl bromide (0.6 mmol) under argon and stirred overnight. The next day, the solvent was evaporated in vacuo and the residue partitioned between aq. NaHCO3 and ethyl acetate. The organic layer was separated, dried with anhydrous sodium sulphate and concentrated to afford the benzylated product which was used as such for the next reaction.
The following compounds were synthesized:
Figure imgf000082_0001
Step 1b:
Figure imgf000082_0002
A mixture of the amine (1.2eq), epoxide (1eq) and Y (NO3)3-6H2O (1 mol %) was stirred at room temperature overnight. The mixture was partitioned between dilute aqueous NaOH and ethyl acetate. The ethyl acetate layer was dried and concentrated, then purified by silica gel chromatography (Combiflash®) with gradient elution using DCM-methanol as solvent.
The following compounds were synthesized:
Figure imgf000083_0001
Step II: Synthesis of 4-f2-(4-benzylDioerazin-1-yl)ethoxy)-3.5- dimethoxybenzaldehvde
Figure imgf000084_0001
To a solution of 4-hydroxy-3,5-dimethoxybenzaldehyde (1.2 g, 6.6 mmol) in 10 mL DCM was added 2-(4-benzylpiperazin-1 -yl)ethanol (1.3 g, 5.94 mmol), Ph3P (2.4 g, 9.0 mmol) and Et3N (1.3 mL, 9.0 mmol) under Argon. The mixture was cooled to 0 0C and diisopropylazodicarobxylate (1.8 mL, 9.0 mmol) was added dropwise. After stirring for 3 - 12 h at room temperature, the mixture was poured into water, extracted with DCM, dried and evaporated. Crude product was subjected to chromatographic purification using Combiflash®. In some cases, the product was contaminated with triphenylphosphine oxide and was carried forward as such for next step.
The following compounds were synthesized:
Figure imgf000084_0002
Figure imgf000085_0001
Step III: Synthesis of 5-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)-3.5-dimethoxybenzyl)- D yrimidine-2.4-diamine:
Figure imgf000086_0001
To a solution of the 4-(2-(4-benzylpiperazin-1-yl)ethoxy)-3,5-dimethoxybenzaldehyde (1.0 mmol) in DMSO (5 ml.) was added 3-anilinopropionitrile (1.2 mmol) under argon. KO'Bu (1.2 mmol) was added to the mixture at 5-10 0C. The reaction was followed by mass spectroscopy. At the disappearance of starting material, the mixture was diluted with water, extracted with ethyl acetate, dried and evaporated. The crude residue was dissolved in absolute EtOH (5 mL). To this was added a solution of guanidine (prepared by treating 3.0 eq. of guanidine hydrochloride with equimolar KO'Bu in 20 mL EtOH and filtering off the solid formed) and refluxed for 24 hours. After cooling to room temperature, the mixture was evaporated and the residue purified by HPLC (preparative RP-HPLC (X-Terra® PrepRPi8 19 x 50 mm column, acetonitrile-water with 0.1% formic acid as solvent).
The following compounds were synthesized:
Figure imgf000086_0002
Figure imgf000087_0001
Step IV: Synthesis of 5-(4-(2-(piperazin-1-yl)ethoxy)-3.5- dimethoxybenzyl)oyrimidine-2.4-diamine:
Figure imgf000088_0001
A suspension of Pd/C (10%) in a solution of 5-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)- 3,5-dimethoxybenzyl)pyrimidine-2,4-diamine (100 mg) in 5 ml_ water containing 50 μl_ AcOH was stirred under Hydrogen atmosphere. Upon disappearance of starting material (vide MS) the mixture was filtered, washed with 5 mL water, and the filtrate concentrated in vacuo and the residue lyophilized.
The following compounds were synthesized:
Figure imgf000088_0002
Figure imgf000089_0001
Step V: Synthesis of 7-(4-(2-(4-((2.4-diaminopyrimidin-5-yl)methyl)-2.6- dimethoxyphenoxy)ethyl)piperazin-1 -yl)- 1 -cyclopropyl-β-fluoro- 1.4-dihydro-4-oxo- 1.8-naohth yridine-3-carboxylic acid.
Method A.
Figure imgf000090_0001
To a solution of 7-chloro-1 -cyclopropyl-6-fluoro-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine- 3-carboxylic acid (20 mg, 0.07 mmol) and 5-(4-(2-(piperazin-1-yl)ethoxy)-3,5- dimethoxybenzyl)pyrimidine-2,4-diamine (25 mg, 0.072 mmol) in NMP (2.0 mL) under argon was added Et3N (32 μL, 0.21 mmol) and TMSCI (24 μ L, 0.14 mmol) and the mixture heated to 1 10C. After 1-3 hours, the mixture was cooled and concentrated in vacuo and the residue re-dissolved in MeOH-Water and subjected to HPLC purification. Fractions bearing the product were combined and concentrated in vacuo and lyophilized.
Method B.
Figure imgf000090_0002
To the amine obtained by hydrogenation from the previous step (0.1 mmol) and a 4- oxoquinoline-3-carboxylic acid (0.1 mmol) and in DMSO (1 mL) was added N- methylmorpholine (32 μL, 0.21 mmol) and heated to 11O0C under argon, until is the reaction is complete (vide HPLC). The mixture was partitioned between ethyl acetate and water. The aqueous fraction was dried and the residue redissolved in MeOH- water mixture then purified by preparative RP-HPLC (X-Terra® PrepRPiβ 19 x 50 mm column) using gradient elution with acetonitrile-water (with 0.1% formic acid) as solvent. Fractions bearing product were combined, concentrated in vacuo and lyophilized.
The following compounds were synthesized according to the above procedures.
Figure imgf000091_0001
Figure imgf000092_0001
* HPLC conditions: Gradient elution using 0-40-100% acetonitrile-water with 0.1% formic acid (0-40% in 5 min, 40-100% in 2.5mi), 1.5mL/min, Xterra® column MSC18, 2.5micron, 4.6x20mm using Agilent 1100 analytical hplc system
Analytical HPLC:
Method A: Gradient elution using 25-100% acetonitrile-water with 0.1% formic acid in 7.5min, 1.5mL/min, Xterra® column MSC18, 2.5micron, 4.6x20mm using Agilent 1100 analytical hplc system. Method B: Gradient elution using 0-40-100% acetonitrile-water with 0.1% formic acid (0-40% in 5 min, 40-100% in 2.5min), 1.5mlJmin, Xterra® column MSC18, 2.5micron, 4.6x20mm using Agilent 1100 analytical hplc system.
Biological Methods
Assays
Minimum inhibitory concentrations (MICs) were determined for all bacterial strains tested using the Clinical Laboratory Standards Institute (CLSI) procedure for broth microdilution. Compounds solutions (test and control) were prepared in 12.5% DMSO, an 8-point, 2-fold dilution series was then prepared from this. 10μl of each concentration was then added to duplicate wells of a 96-well, flat-bottomed microtitre plate.
Bacterial strains were prepared by colony suspension to an optical density equivalent to a 0.5 McFarland Standard, and then diluted in cation-adjusted Mueller-Hinton broth (CAMHB) that had been supplemented with 0.0022% Tween-80. 90μl of this inoculum was added to each test well. The final concentration of cells was 5.5 x 10s CFU/mL.
Plates were incubated for 20-24h at 350C. The MIC was recorded as the lowest concentration of compound that prevented visible growth from occurring in duplicate wells.
S. aureus 29213 and E. coli 25922 are sensitive to ciprofloxacin (CIP) and TMP and were obtained from the American Type Culture Collection (ATCC), Manassus, VA, USA.
All other strains were obtained from the Network of Antimicrobial Surveillance in Stahpylococcus aureus (NARSA) Hemdon, VA, USA:
S. aureus NRS19 is sensitive to TMP but resistant to CIP. S. epidermidis NRS60 is sensitive to CIP but resistant to TMP.
S. aureus NRS119 is resistant to both CIP and TMP.
Biological Data
Biological data were obtained using the antibacterial assays described above for the following compounds: BP-4Q-001 through BP-4Q-012 as well as for CIP, TMP and an equimolar mixture of CIP/TMP.
For the S. aureus 29213 assay, all of the compounds had a minimum inhibitory concentration of less than 20 μg/ml.
For the S. aureus 29213 assay, the following compounds had a minimum inhibitory concentration of less than 10 μg/ml: BP-4Q-001 , BP-4Q-002, BP-4Q-003, BP-
4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
For the S. aureus 29213 assay, the following compounds had a minimum inhibitory concentration of less than 5 μg/ml: BP-4Q-002, BP-4Q-003, BP-4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
For the S. aureus 29213 assay, the following compounds had a minimum inhibitory concentration of 1 μg/ml or less: BP-4Q-001, BP-4Q-002, BP-4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
One compound, compound BP-4Q-002, had a minimum inhibitory concentration of 0.5 μg/ml.
CIP had a minimum inhibitory concentration of 0.5 μg/ml. TMP had a minimum inhibitory concentration of 2 μg/ml. The equimolar mixture of CIP/TMP had a minimum inhibitory concentration of 0.5 μg/ml. These results show that all of the compounds provide antibacterial activity against a strain sensitive to CIP and TMP. The activity of many of the compounds is comparable or better than CIP, TMP and an equimolar mixture of CIP/TMP.
For the E. coli 25922 assay, all of the compounds had a minimum inhibitory concentration of less than 20 μg/ml.
For the E. coli 25922 assay, the following compounds had a minimum inhibitory concentration of less than 10 μg/ml: BP-4Q-001 , BP-4Q-002, BP-4Q-003, BP- 4Q-004, BP-4Q-005, BP-4Q-007, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP- 4Q-012.
For the E. coli 25922 assay, the following compounds had a minimum inhibitory concentration of less than 5 μg/ml: BP-4Q-002, BP-4Q-003, BP-4Q-004, BP-4Q-005, BP-4Q-007, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
One compound, compound BP-4Q-002, had a minimum inhibitory concentration of 1 μg/ml.
CIP had a minimum inhibitory concentration of 0.0078 μM. TMP had a minimum inhibitory concentration of 1 μg/ml. The equimolar mixture of CIP/TMP had a minimum inhibitory concentration of <0.125 μM.
These results show that all of the compounds provide antibacterial activity against a strain sensitive to CIP and TMP. The activity of many of the compounds is comparable to TMP.
For the S. aureus NRS19 assay, the following compounds had a minimum inhibitory concentration of less than 20 μg/ml: BP-4Q-001, BP-4Q-002, BP-4Q-003, BP- 4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012. For the S. aureus NRS19 assay, the following compounds had a minimum inhibitory concentration of less than 10 μg/ml: BP-4Q-001 , BP-4Q-002, BP-4Q-004, BP- 4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP- 4Q-012.
For the S. aureus NRS19 assay, the following compounds had a minimum inhibitory concentration of less than 5 μg/ml: BP-4Q-002, BP-4Q-004, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
One compound, compound BP-4Q-002, had a minimum inhibitory concentration of 1 μg/ml.
CIP had a minimum inhibitory concentration of 32 μg/ml M. TMP had a minimum inhibitory concentration of 4 μg/ml. The equimolar mixture of CIP/TMP had a minimum inhibitory concentration of 8 μg/ml.
These results show that all of the compounds provide antibacterial activity against a strain sensitive to TMP but resistant to CIP. The activity of many of the compounds is comparable or significantly better than CIP, TMP and an equimolar mixture of CIP/TMP.
For the S. epdermidis NRS60 assay, all of the compounds had a minimum inhibitory concentration of less than 20 μg/ml.
For the S. epdermidis NRS60 assay, the following compounds had a minimum inhibitory concentration of less than 5 μg/ml: BP-4Q-001 , BP-4Q-002, BP-4Q-004, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
One compound, compound BP-4Q-002, had a minimum inhibitory concentration of 2 μg/ml. CIP had a minimum inhibitory concentration of 0.25 μg/ml. TMP had a minimum inhibitory concentration of >64 μg/ml. The equimolar mixture of CIP/TMP had a minimum inhibitory concentration of 0.25 μg/ml.
These results show that all of the compounds provide antibacterial activity against a strain sensitive to CIP but resistant to TMP. The activity of all of the compounds is significantly better than TMP. The activity of some of the compounds is comparable to CIP and an equimolar mixture of CIP/TMP.
The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.
REFERENCES
A number of patents and publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Huovinen, P., et a/., 1992, "Synergism of Trimethoprim and Ciprofloxacin in Vitro against Clinical Bacterial Isolates" Eur. J. Clin. Microbiol. Infect. Pis.. Vol. 11 , pp. 255-257.
WO2005/070940, "Rifamycin derivatives effective against drug-resistant microbes". WO96/16046, "Novel benzyl pyrimidines".
US2006019986, "(R/S) Rifamycin Derivatives, their preparations and pharmaceutical compositions".

Claims

CLAIMS:
1. A compound of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
NH,
Figure imgf000099_0001
(I)
wherein:
each of -R1 and -R3 is independently -ORA
and wherein:
-R2 is independently -Br or -ORA
wherein:
each -RA is independently saturated aliphatic
Figure imgf000099_0002
alkyl or -L-A;
and wherein at least one of -R1, -R2 and -R3 is -O-L-A
wherein:
-L- is independently -L1 -L2- or -L2-
wherein: -L1- is independently -L1C- or -L1H-, -L2- is independently -L2H- or -L2*-
wherein:
-L1C- is independently saturated aliphatic C1-4 alkylene and is optionally substituted,
-L1H- is independently -L1Z-, -L1C-L1Z- or -L1C-L1Z-L1C-,
10 wherein:
-L1Z- is independently -O-, -NRL1Z- or -NC(O)RL1Z-,
15 wherein:
-RL1Z-, if present, is independently -H, saturated or unsaturated aliphatic Ci.6alkyl, or Gnoaryl, and is 20 optionally substituted,
and wherein:
-L2H- is independently saturated or unsaturated C4-7 25 heterocyclylene and is optionally substituted,
-L2X- is independently
Figure imgf000100_0001
wherein RL2X, if present, is independently saturated or 30 unsaturated aliphatic Ci-4alkyl and is optionally substituted, and wherein:
-A is independently a 4-quinolonyl or 4H-4-oxoquinolizinyl.
2. A compound according to claim 1 , wherein -R2 is independently -O-L-A; each of -R2 and -R3 is -OMe; -L1H- is independently -L1C-L1Z- or -L1C-L1Z-L1C-;
-L1Z- is independently -O- or -NRL1Z-; wherein -RL1Z-, if present, is independently -H, or saturated or unsaturated aliphatic d^alkyl; L2- is independently -L2H-; and _|_2H- is independently saturated or unsaturated C^heterocyclylene wherein one or more ring atoms are N, and is optionally substituted.
3. A compound according to claim 2, wherein -L- is independently -U-L2-.
4. A compound according to claim 3, wherein -L1H- is independently -L1C-L1Z-L1C-.
5. A compound according to claim 4, wherein -L1Z- is independently -O-.
6. A compound according to claim 5, wherein
-L2H- is independently selected from the following, wherein, if present, -R12^ is independently -CH2-NH2, -OH or =N-OH and R2LHB is independently -CH2-NH2 or - OH:
Figure imgf000102_0001
7. A compound according to any one of the preceding claims, wherein -L- is independently -L2-.
8. A compound according to any one of the preceding claims, wherein -A is independently -A1 wherein -A1 is:
Figure imgf000102_0002
wherein:
each of Q2, Q6 and Q8 is independently C or N;
and wherein:
-RQ1 is independently cyclopropyl, saturated aliphatic Ci-4alkyl, phenyl, pyridinyl, and is optionally substituted, or (a) together with -RQ8 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic Cwsheterocycle and is optionally substituted, or (b) together with -R02 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted;
and wherein: -RQ2, if present, and if Q2 is C, is independently -H or together with -RQ1 and the atoms to which they are connected forms a saturated or unsaturated alicyclic C^heterocycle and is optionally substituted;
and wherein:
-R05, if present, is independently -H, -Me, or -NH2;
and wherein:
-RQ6, if present, and if Qβ is C, is independently -H or -F;
and wherein:
-RQ8, if present, and if Q8 is C, is independently -H, -F, -Cl, -OMe,
-OCH2F, -OCHF2, -OCF3, -CF3, -CN or together with -RQ1 and the atoms to which they are attached, forms a saturated or unsaturated alicyclic C^heterocycle, and is optionally substituted
9. A compound according to claim 8, wherein Q2 is independently C;
Q6 is independently C; Q8 is independently C or N; -RQ2, if Q2 is C, is independently -H; and
-RQ5 is independently -H.
10. A compound according to claim 9, wherein
-RQ1 is independently cyclopropyl, and is optionally substituted; -R08, if Q8 is C, is independently -H.
1 1. A compound according to claim 9 or claim 10, wherein -RQ6, if Q6 is C, is independently -F.
12. A compound according to any one of the preceding claims, wherein -L- is independently selected from:
Figure imgf000104_0001
and
-A is independently selected from:
Figure imgf000104_0002
13. A compound according to any one of the preceding claims, wherein the compound is selected from BP-4Q-001 , BP-4Q-002, BP-4Q-003, BP-4Q-004, BP- 4Q-005, BP-4Q-006, BP-4Q-007, BP-4Q-008, BP-4Q-009, BP-4Q-010, BP-4Q-011 and BP-4Q-012.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, and a pharmaceutically acceptable carrier, diluent, or excipient.
15. A method of treatment of a bacterial infection or disease comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 14.
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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2014178008A1 (en) 2013-05-02 2014-11-06 Actelion Pharmaceuticals Ltd Quinolone derivatives
CN110551124A (en) * 2019-06-14 2019-12-10 山东省联合农药工业有限公司 quinolone compound or agriculturally and pharmaceutically acceptable salt thereof, and preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996016046A2 (en) * 1994-11-24 1996-05-30 F. Hoffmann-La Roche Ag Novel benzyl pyrimidines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996016046A2 (en) * 1994-11-24 1996-05-30 F. Hoffmann-La Roche Ag Novel benzyl pyrimidines

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014178008A1 (en) 2013-05-02 2014-11-06 Actelion Pharmaceuticals Ltd Quinolone derivatives
US9540399B2 (en) 2013-05-02 2017-01-10 Actelion Pharmaceuticals Ltd. Quinolone derivatives
CN110551124A (en) * 2019-06-14 2019-12-10 山东省联合农药工业有限公司 quinolone compound or agriculturally and pharmaceutically acceptable salt thereof, and preparation method and application thereof

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