WO2016189304A1 - Composés antibactériens - Google Patents

Composés antibactériens Download PDF

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Publication number
WO2016189304A1
WO2016189304A1 PCT/GB2016/051514 GB2016051514W WO2016189304A1 WO 2016189304 A1 WO2016189304 A1 WO 2016189304A1 GB 2016051514 W GB2016051514 W GB 2016051514W WO 2016189304 A1 WO2016189304 A1 WO 2016189304A1
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independently
compound
alkyl
group
mmol
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PCT/GB2016/051514
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English (en)
Inventor
Ian Cooper
Rolf Peter Walker
Mark Pichowicz
Andrew James Ratcliffe
Frederik Deroose
Charles John Robert Hedgecock
Peter Brandt
Johan Georg GISING
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Redx Pharma Plc
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Publication of WO2016189304A1 publication Critical patent/WO2016189304A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • Antibacterial compounds This invention relates to antibacterial drug compounds containing a polycyclic ring system incorporating a macrocyclic ring. It also relates to pharmaceutical formulations of antibacterial drug compounds. It also relates to uses of the derivatives in treating bacterial infections and in methods of treating bacterial infections. The invention is also directed to antibacterial drug compounds which are capable of treating bacterial infections which are currently hard to treat with existing drug compounds. Such infections are frequently referred to as resistant strains. The increasing occurrence of bacterial resistance to antibiotics is viewed by many as being one of the most serious threats to the future health and happiness of centuries. Multidrug resistance has become common among some pathogens, e.g.
  • Staphylococcus aureus Streptococcus pneumoniae, Clostridium difficile and Pseudomonas aeruginosa.
  • Staphylococcus aureus a Gram positive bacterium
  • MRSA methicillin resistant Staphylococcus aureus
  • antibiotic resistant Gram negative strains such as either Escherichia coli NDM-1 (New Delhi metallo- ⁇ -lactamase) or Klebsiella pneumoniae NDM-1
  • Escherichia coli NDM-1 New Delhi metallo- ⁇ -lactamase
  • Klebsiella pneumoniae NDM-1 are also very difficult to treat.
  • antibiotics such as vancomycin and colistin are effective against these strains.
  • the fluoroquinolone antibacterial family are synthetic broad-spectrum antibiotics. They were originally introduced to treat Gram negative bacterial infections, but are also used for the treatment of Gram positive strains.
  • One problem with existing fluoroquinolones can be the negative side effects that may sometimes occur as a result of fluoroquinolone use. In general, the common side-effects are mild to moderate but, on occasion, more serious adverse effects occur.
  • CNS central nervous system
  • MRSA central nervous system
  • ⁇ -lactam antibiotics such as methicillin.
  • Bacterial resistance is also becoming a problem in the treatment of animals. Antibacterials find widespread use in industrial farming, e.g. to prevent mastitis in dairy cattle, where they are often used prophylactically. Such widespread prophylactic use has led to the build-up of resistance in certain bacterial strains which are particularly relevant to animal health.
  • a further aim of certain embodiments of this invention is to provide antibiotics in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe). Certain embodiments of the present invention satisfy some or all of the above aims.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof:
  • group A is selected from a 5-12heterocycloalkyl group comprising at least one nitrogen in the ring system and a 3-6heteroalkyl group comprising at least one nitrogen in the linking chain;
  • L 3 is attached by a covalent bond to an atom selected from the nitrogen and carbon atoms which form the group A ring system or linking chain;
  • Z is independently selected from N and CR 2 ;
  • R 1 and R 2 are each independently selected from: H, C1-C4-alkyl, halogen, OR 8 , NR 8 R 9 and C 1 -C 4 -haloalkyl;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from: N and CR 10 ; wherein no more than two of X 1 , X 2 , X 3 and X 4 are N; wherein a single one of X 3 and X 4 is a carbon atom attached by a covalent bond to Y 1 ;
  • Y 1 is
  • the compound of formula (I) may be a compound of formula (II): (II); wherein L 3 is attached by a covalent bond to an atom selected from N a , C a , C b and C c ; wherein if L 3 is attached to N a , R 3 is absent; and wherein the positions on C a , C b and C c to which L 3 is not attached are occupied by R 5 groups; Z is independently selected from N and CR 2 ; R 1 and R 2 are each independently selected from: H, C 1 -C 4 -alkyl, halogen, OR 8 , NR 8 R 9 and C1-C4-haloalkyl; R 3 is absent (if L 3 is joined to N a ) or is independently selected from H and C1-C4-alkyl; R 4 is independently selected from: H, C1-C4-alkyl, F, NR 8 R 9 , OR 8 , C1-C4-haloalkyl and CO
  • linker group L 3 is arranged such that the group Y 1 is attached to the end of linker group L 3 which is defined as (CR 5 R 5 ) s .
  • the atom N a , C a , C b or C c is attached to the end of linker group L 3 which is defined as (CR 5 R 5 )u.
  • C a could be described as a C(R 5 ) x group
  • C b (if present) could be described as a C(R 5 ) y group
  • C c could be described as a C(R 5 )z group
  • x and y are each an integer selected from 1 and 2
  • z is an integer selected from 0 and 1, with the values of x, y and z being selected to satisfy valency requirements.
  • the macrocyclic ring is the ring including the atoms or groups represented by L 1 , L 3 , Y 1 ,and X 4 .
  • the macrocyclic ring may also include one or more of the atoms or groups represented by N a , C a , C b , C c and X 3 .
  • the compound may be the E geometric isomer, the Z geometric isomer or a mixture thereof.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , Y 1 , X 1 , X 2 and X 4 are as defined above for formula (II).
  • r may be 2.
  • the compound of formula (I) may be a compound of formula (IV):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , Y 1 , X 1 , X 2 and X 4 are as defined above for formula (II).
  • r may be 2.
  • the compound of formula (I) may be a compound of formula (V):
  • r may be 2.
  • the compound of formula (I) may be a compound of formula (VI):
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , Y 1 , X 1 , X 2 , and X 4 are as defined above for formula (II) and wherein R 4 is independently selected from: H, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and CO 2 R 8 ; or R 3 and R 4 together form a–(CR 5 R 5 ) n - group; wherein n is an integer selected from 1, 2 and 3.
  • r may be 2.
  • the compound of formula (I) may be a compound of formula (VII):
  • R 1 , R 2 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , Y 1 , X 1 , X 2 , X 4 and n are as defined above for formula (II) and wherein L 3 is attached by a covalent bond to an atom selected from C a , Cb and C c .
  • r may be 2.
  • the compound of formula (I) may be a compound of formula (VIII):
  • r may be 3.
  • the compound of formula (I) may be a compound of formula (IX):
  • R 1 , R 2 , R 5 , X 1 , X 2 , X 4 , Y 1 , L 1 , L 3 , L 2 , n and R 7 are as defined for formula (II) above; wherein L 3 is attached by a covalent bond to an atom selected from C d , C e and C f and wherein the positions on C d , C e and C f to which L 3 is not attached are occupied by R 5 groups.
  • the compound of formula (I) may be a compound of formula (X):
  • R 1 , R 2 , R 5 , X 1 , X 2 , X 4 , Y 1 , L 1 , L 3 , n and R 7 are as defined for formula (II) above; wherein X a is carbon or nitrogen; and wherein L 3 is attached by a covalent bond to an atom selected from C g , C h and, where X a is carbon, X a and wherein any positions on C g , C h and X a to which L 3 is not attached are occupied by R 5 groups.
  • the compound of formula (I) may be a compound of formula (XI):
  • L 3 is attached by a covalent bond to an atom selected from C a , C b and C c ; and wherein the positions on C a , C b and C c to which L 3 is not attached are occupied by R 5 groups; R 1 , R 2 , R 5 , R 6 and R 8 are each independently at each occurrence selected from: H and C1- C 4 -alkyl; X 1 , X 2 and X 4 are each independently selected from: N and CR 10 ; wherein no more than two of X 1 , X 2 and X 4 are N; L 1 is a linker group having the form -(CR 5 R 5 ) r -; wherein r is an integer selected from 2 and 3; L 3 is independently –(CR 5 R 5 ) s -Y 3 -(CR 5 R 5 ) t -Y 2 -(CR 5 R 5 ) u -; wherein s and t are each independently an integer selected from 1, 2, 3 and
  • group A may be a 5-, 6- or 7-membered heterocycloalkyl ring comprising at least one nitrogen in the ring.
  • Group A may be a piperidine, piperazine or pyrrolidine ring. It may be that the group L 1 is attached to the nitrogen or a nitrogen in the group A ring, e.g. the nitrogen or a nitrogen in the 5-, 6- or 7-membered heterocycloalkyl ring (e.g. a piperidine, piperazine or pyrrolidine ring).
  • Group A may be a 3-6 heteroalkyl group comprising at least one nitrogen in the linking chain. It may be that the group L 1 is attached to the nitrogen or a nitrogen in the group A ring.
  • L 3 is attached to C a .
  • a single R 5 group is also attached to C a , two R 5 groups are attached to C b and a single R 5 group is attached to C c , i.e. x is 1, y is 2 and z is 0.
  • L 3 is attached to C b .
  • a single R 5 group is also attached to C b , two R 5 groups are attached to C a and a single R 5 group is attached to C c , i.e. x is 2, y is 1 and z is 0.
  • L 3 is attached to C b
  • m is 1. It may be that L 3 is attached to N a .
  • R 5 groups are attached to C a
  • two R 5 groups are attached to C b and a single R 5 group is attached to C c , i.e. x is 2, y is 2 and z is 1.
  • L 3 is attached to C c .
  • two R 5 groups are attached to C a and two R 5 groups are attached to C b , i.e. x is 2, y is 2 and z is 0.
  • L 3 is attached to C a , C b or C c .
  • X 3 is a carbon atom which is attached by a covalent bond to Y 1 .
  • X 1 , X 2 and X 4 are each independently selected from: N and CR 10 ; wherein no more than two of X 1 , X 2 and X 4 are N. It may be that each of X 1 , X 2 and X 4 are CR 10 . It may be that X 1 is N.
  • X 1 is CR 10a , wherein R 10a is independently selected from: H, halo, nitro, cyano, NR 8 R 9 , OR 8 ; O-aryl, SR 8 , SOR 8 , SO3R 8 , SO2R 8 , SO2NR 8 R 8 , CO2R 8 , C(O)R 8 , CONR 8 R 8 , aryl, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and C 1 -C 4 -haloalkyl.
  • R10a may be selected from H, halo, C1-C4-alkyl and C1-C4-haloalkyl.
  • X 1 may be CH. It may be that X 2 is N.
  • X 2 is CR 10b , wherein R 10b is independently selected from: H, halo, nitro, cyano, NR 8 R 9 , OR 8 ; O-aryl, SR 8 , SOR 8 , SO3R 8 , SO2R 8 , SO2NR 8 R 8 , CO2R 8 , C(O)R 8 , CONR 8 R 8 , aryl, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and C 1 -C 4 -haloalkyl.
  • R10b may be selected from H, halo, C1-C4-alkyl and C1-C4-haloalkyl.
  • X 2 may be CH. It may be that X 4 is N.
  • X 4 is CR 10c , wherein R 10c is independently selected from: H, halo, nitro, cyano, NR 8 R 9 , OR 8 ; O-aryl, SR 8 , SOR 8 , SO 3 R 8 , SO 2 R 8 , SO 2 NR 8 R 8 , CO 2 R 8 , C(O)R 8 , CONR 8 R 8 , aryl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4-haloalkyl.
  • R10c may be selected from H, halo, C1-C4-alkyl and C1-C4-haloalkyl.
  • X 4 may be CH. It may be that X 1 , X 2 and X 4 are each CH. It may be that X 1 , X 2 and X 4 are each CH and R 1 and R 2 are each H.
  • R 10 may be independently at each occurrence selected from H, halo, C1-C4-alkyl and C1-C4- haloalkyl. R 10 may at all occurrences be H.
  • Z is CR 2 . It may be that R 1 is H. It may be that R 2 is H, i.e. that Z is CH.
  • R 1 and R 2 are each H, i.e. that R 1 is H and Z is CH.
  • Y 1 may be selected from O and CR 5 R 5 .
  • Y 1 may be selected from O, S and NR 9 .
  • Y 1 is CR 5 R 5 .
  • Y 1 is CH 2 .
  • Y 1 is O.
  • r may be 2.
  • r may be 3.
  • each R 5 group in the linker L 1 is H.
  • L 1 may be–(CH2)2-.
  • L 1 may be–(CH2)3-.
  • m may be 0.
  • m may be 1.
  • L 5 may be absent.
  • L 5 is -L 6 -L 2 -; L 6 may be absent.
  • L 6 is–L 4 NR 6 -; L 4 may be a bond. This will typically be the case where R 3 and R 4 do not together form a– (CR 5 R 5 )n- group.
  • L 4 may be–CR 5 R 5 -. This may be the case where R 3 and R 4 together form a–(CR 5 R 5 )n- group.
  • u 1.
  • u 0.
  • s is 1.
  • t is an integer selected from 1, 2 and 3.
  • s is an integer selected from 2, 3 and 4.
  • t is an integer selected from 2, 3 and 4.
  • Y 2 is selected from O, NR 9 and S. It may be that Y 2 is O. In these embodiments, it may be that u is 1. It may be that R 5 is, at each occurrence in the group- (CR 5 R 5 )u-, H. These embodiments are particularly preferred where L 3 is attached to C a , C b or C c . It may be that the group -(CR 5 R 5 ) u - is–C(O)- and that Y 2 is selected from O and NR 9 . Thus it may be that Y 2 is NR 9 , e.g. NH. In these embodiments, it may be that Y 3 is a bond. Alternatively, it may be that Y 2 is a bond.
  • Y 2 is a bond.
  • L 3 is attached to N a and Y 3 is selected from O, NR 9 and S, it may be that u is 0 and Y 2 is a bond. It may be that Y 3 is a bond. Alternatively, it may be that Y 3 is selected from O, NR 9 and S. It may be that Y 3 is O. It may be that u is 0, Y 2 is a bond and Y 3 is selected from O, NR 9 and S (e.g. is O).
  • L 3 is attached to N a , it may be that u is 0, Y 2 is a bond and Y 3 is selected from O, NR 9 and S (e.g. Y 3 is O).
  • L 3 is attached to C a , C b or C c , it may be that u is 1, Y 2 is selected from O, NR 9 and S (e.g. is O) and Y 3 is a bond. It may be that Y 1 and Y 2 are each independently selected from O, NR 9 and S (e.g. are each O), Y 3 is a bond, u is 1, s is 1 and t is an integer selected from 1, 2 and 3. In these embodiments, it may be that L 3 is attached to C a , C b or C c . It may be that Y 1 and Y 3 are each independently selected from O, NR 9 and S (e.g.
  • Y 2 is a bond
  • u is 0,
  • s and t are each independently an integer selected from 2, 3, and 4.
  • L 3 is attached to N a .
  • Y 2 and Y 3 are each a bond.
  • Y 2 and Y 3 are each a bond and u is 0.
  • s is an integer selected from 1 and 2
  • t is an integer selected from 1, 2, 3 and 4.
  • Y 1 is O.
  • Y 1 is CR 5 R 5 .
  • Y 3 is 1,2,3-triazole.
  • the triazole may have a structure selected from:
  • Y 3 has the structure Where Y 3 is 1,2,3- triazole, it may be that s and t are each 1. Where Y 3 is 1,2,3-triazole, it may be that Y 2 is a bond. Where Y 3 is 1,2,3-triazole, it may be that Y 2 is a–O-. Where Y 3 is 1,2,3-triazole, it may be that s, t and u are each 1 and Y 2 is -O-.
  • R3 is independently selected from H and C1-C4-alkyl.
  • R 3 may be H.
  • R 3 may be C 1 -C 4 -alkyl, e.g. methyl.
  • L 4 is a bond
  • m is 0.
  • R 3 and R 4 together form a–(CR 5 R 5 )n- group; wherein n is an integer selected from 1, 2 and 3. It may be that n is 2. It may be that each R 5 group is the group formed by R 3 and R 4 is H. Thus, it may be that R 3 and R 4 together form a–CH2CH2- group. In these embodiments, it may be that m is 1. In these embodiments, it may be that L 4 is–CR 5 R 5 -. L 2 is preferably–CR 5 R 5 - and most preferably is -CH 2 -. Alternatively, L 2 may be a 3-, 4- or 5- membered cycloalkyl ring, e.g. a 4-membered cycloalkyl ring.
  • R 7 may be a monocyclic aryl group.
  • R 7 may be a phenyl group.
  • Said phenyl group may be unsubstituted or it may be substituted with from 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR a R a , NR a S(O)2R a , NR a CONR a R a , NR a CO2R a , NR a C(O)R a , OR a ; SR a , SOR a , SO3R a , SO 2 R a , SO 2 NR a R a , CO 2 R a C(O)R a , CONR a R a , C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -
  • R 7 may be a phenyl group which is substituted by 1 to 3 substituents independently at each occurrence selected from F, nitro, C 1 -C 4 -alkyl, C 2 -C 4 - alkenyl, C2-C4-alkynyl and C1-C4-haloalkyl.
  • exemplary R 7 groups include 2,5-difluorophen-1-yl and 3-nitro-4-methylphen-1-yl.
  • R 7 is a bicyclic carbocyclic or heterocyclic ring system in which at least one of the two rings is aromatic or heteroaromatic.
  • R 7 may take the form:
  • V 1 , V 2 and V 3 are each independently selected from: N and CR 11 ; with the proviso that no more than two of V 1 , V 2 and V 3 are N; and wherein the ring B is a substituted or unsubstituted 5- or 6- membered saturated cycloalkyl or heterocycloalkyl ring.
  • R 11 is independently at each occurrence selected from: H, halo, nitro, cyano, NR a R a , NR a S(O)2R a , NR a C(O)R a , NR a CONR a R a , NR a CO 2 R a , OR a ; SR a , SOR a , SO 3 R a , SO 2 R a , SO 2 NR a R a , CO 2 Ra C(O)R a , CONR a R a , CR b R b NR a R a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4- haloalkyl.
  • R 7 takes the form:
  • V 4 and V 5 are each independently selected from O, S, CR 12 R 12 and NR 8 ;
  • p is an integer selected from 1 and 2.
  • R 7 takes the form:
  • V 1 , V 2 and V 3 are each independently selected from: N and CH; with the proviso that no more than two of V 1 , V 2 and V 3 are N.
  • a single one of V 1 , V 2 and V 3 is N.
  • V 3 is CR 11 (e.g. CH).
  • V 1 is N and V 2 is CR 11 (e.g. CH).
  • V 2 is N and V 1 is CR 11 (e.g. CH).
  • V 2 is nitrogen.
  • V 3 is CR 11 .
  • V 1 is CR 11 .
  • R 11 is selected from H, methyl and halogen, e.g. F.
  • R 11 is selected from H and halogen, e.g. F. It may be that V 3 is CH. It may be that V 1 is CR 11 , wherein R 11 is selected from H and halogen, e.g. F. It may be that V 2 is nitrogen, V 3 is CH and V 1 is CR 11 , wherein R 11 is selected from H and halogen, e.g. F.
  • V 4 is O. Thus, it may be that both V 4 and V 5 are O.
  • Exemplary R 7 groups include:
  • R 7 may also take the form
  • V 6 is independently selected from N and CR 13 (e.g. CH); V 7 is independently selected from NR 8 , S and O; and R 13 is independently at each occurrence selected from: halo, nitro, cyano, NR a R a , NR a S(O)2R a , NR a C(O)R a , NR a CONR a R a , NR a CO 2 R a , NR a C(O)R a , OR a ; SR a , SOR a , SO 3 R a , SO 2 R a , SO 2 NR a R a , CO 2 Ra C(O)R a , CONR a R a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, and CR a R a NR a R a
  • R 13 may be independently at each occurrence selected from F, CN, OR a , nitro, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and C 1 -C 4 -haloalkyl.
  • R 6 is selected from H or C1-C4-alkyl. Even more preferably, R 6 is H. It may be that R 8 is independently at each occurrence selected from H or C1-C4-alkyl. It may be that R 8 is at each occurrence H. It may be that R 9 is independently at each occurrence selected from H, C1-C4-alkyl, C1-C4- haloalkyl, S(O) 2 R 8 and C(O)R 8 . It may be that R 9 is independently at each occurrence selected from H, C1-C4 alkyl (e.g. methyl) and C(O)R 8 (e.g. acetate).
  • C1-C4 alkyl e.g. methyl
  • C(O)R 8 e.g. acetate
  • R 9 is at each occurrence H. It may be that L 1 , group A, r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 13 atoms. It may be that L 1 , group A, r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 14 atoms. It may be that L 1 , group A, r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 15 atoms.
  • L 1 , group A, r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 16 atoms. It may be that L 1 , group A, r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 17 atoms. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 13 atoms.
  • r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 13 atoms and R 3 and R 4 together form a–(CR 5 R 5 )n- group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 13 atoms and R 3 and R 4 do not together form a–(CR 5 R 5 ) n - group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 14 atoms.
  • r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 14 atoms and R 3 and R 4 together form a–(CR 5 R 5 ) n - group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 14 atoms and R 3 and R 4 do not together form a–(CR 5 R 5 ) n - group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 15 atoms.
  • r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 15 atoms and R 3 and R 4 together form a–(CR 5 R 5 )n- group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 15 atoms and R 3 and R 4 do not together form a–(CR 5 R 5 )n- group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 16 atoms.
  • r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 16 atoms and R 3 and R 4 together form a–(CR 5 R 5 )n- group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 16 atoms and R 3 and R 4 do not together form a–(CR 5 R 5 )n- group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 17 atoms.
  • r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 17 atoms and R 3 and R 4 together form a–(CR 5 R 5 ) n - group. It may be that r, s, t, u, Y 2 and Y 3 are selected such that the macrocyclic ring has a ring size of 17 atoms and R 3 and R 4 do not together form a–(CR 5 R 5 ) n - group.
  • the compound of formula (I) may have a structure selected from:
  • the compound of formula (I) is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 in the Examples below.
  • the compound of the invention is an N-oxide
  • it will typically be a pyridine N-oxide, i.e. where the compound of the invention comprises a pyridine ring (which may form part of a bicyclic or tricyclic ring system), the nitrogen of that pyridine may be N + -O-.
  • the compound of the invention is not an N-oxide. Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • acid addition or base salts wherein the counter ion is optically active for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.
  • the oxime groups present in certain compounds of the invention may be present as the E-oxime, as the Z- oxime or as a mixture of both in any proportion.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. Where structurally isomeric forms of a compound are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety.
  • tautomerism tautomeric isomerism
  • racemate or the racemate of a salt or derivative
  • HPLC high pressure liquid chromatography
  • the racemate or a racemic precursor
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted into the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example,“Stereochemistry of Organic Compounds” by E. L.
  • Cm-Cn refers to a group with m to n carbon atoms.
  • alkyl refers to a linear or branched hydrocarbon chain.
  • C 1- C 6 -alkyl may refer to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n- hexyl.
  • the alkyl groups may be unsubstituted or substituted by one or more substituents.
  • haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • C1-C6-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g.1-chloroethyl and 2-chloroethyl, trichloroethyl e.g.1,2,2-trichloroethyl, 2,2,2- trichloroethyl, fluoroethyl e.g. 1-fluoroethyl and 2-fluoroethyl, trifluoroethyl e.g.
  • haloalkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one fluorine atom.
  • alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond.
  • the double bond(s) may be present as the E or Z isomer (e.g. cis or trans).
  • the double bond may be at any chemically possible position of the hydrocarbon chain.
  • “C 2- C 6 -alkenyl” may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • the alkenyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon in each alkenyl group independently may be fluorine, OR a or NR a R a .
  • alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond.
  • the triple bond may be at any possible position of the hydrocarbon chain.
  • “C 2- C 6 -alkynyl” may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • the alkynyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon in each alkynyl group independently may be fluorine, OR a or NR a R a .
  • carbocylic refers to a group consisting of one or more rings which are entirely formed from carbon atoms.
  • a carbocylic group can be a mono- or bicyclic cycloalkyl group, or it can comprise at least one phenyl ring.
  • heterocyclic refers to a group consisting of one or more rings wherein the ring system includes at least one heteroatom.
  • a heterocyclic group may comprise either a heteroaryl or heterocycloalkyl rings.
  • cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms.
  • C 3 -C 6 -cycloalkyl may refer to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl groups may be unsubstituted or substituted by one or more substituents.
  • Specific substituents for each cycloalkyl group independently may be oxo, C1-C4-alkyl, fluorine, OR a or NHR a .
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • aryl refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the“aryl” may be phenyl and naphthyl. Equally, aryl groups may include non-aromatic carbocyclic portions.
  • the aryl group may be unsubstituted or substituted by one or more substituents.
  • Specific substituents for each aryl group independently may be C1-C4-alkyl, C1-C4-haloalkyl, cyano, halogen, OR a or NHR a .
  • heteroaryl may refer to any aromatic (i.e. a ring system containing (4n + 2) ⁇ - or n- electrons in the ⁇ -system) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N).
  • any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from O, S and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms.
  • heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.
  • Heteroaryl groups may also be 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1 heteroatomic group independently selected from O, S and NH and the ring also comprises a carbonyl group. Such groups include pyridones and pyranones.
  • the heteroaryl system itself may be substituted with other groups.
  • the heteroaryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each heteroaryl group independently may be C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, cyano, halogen, OR a or NHR a .
  • m-nheterocycloalkyl may refer to a m- to n-membered monocyclic or bicyclic saturated or partially saturated group comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring system are selected from O, S and N).
  • partially saturated it is meant that the ring may comprise one or two double bonds. This applies particularly to monocyclic rings with from 5 to 8 members. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom.
  • heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine.
  • Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon or nitrogen atoms; or they may be share a bridgehead, i.e. the rings are linked to each other through two non-adjacent carbon or nitrogen atoms.
  • heterocycloalkyl groups may be unsubstituted or substituted by one or more substituents.
  • Specific substituents for each heterocycloalkyl group may independently be oxo, C 1 -C 4 - alkyl, fluorine, OR a or NHR a .
  • 3-6 heteroalkyl refers to a 3- to 6- membered chain of atoms, wherein at least one of said atoms is a heteroatom, e.g. a nitrogen, and wherein the remainder of said atoms are carbon atoms.
  • the compound of formula (I) is an N-oxide
  • it will typically be a pyridine N-oxide, i.e. the nitrogen of the pyridine may be N + -O-.
  • the compound of the invention is not an N-oxide.
  • An aromatic ring is a phenyl ring.
  • the present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XI) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Certain isotopically-labelled compounds for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e.
  • isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • each of the compounds of the present invention may be used as a medicament.
  • compound as defined above for the treatment of bacterial infections The compounds and formulations of the present invention may be used in the treatment of a wide range of bacterial infections.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of bacteria.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram positive bacteria.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram negative bacteria.
  • the compounds and formulations of the invention may be used to treat infections caused by bacteria which are in the form of a biofilm.
  • resistant strains is intended to mean strains of bacteria which have shown resistance to one or more known antibacterial drug. For example, it may refer to strains which are resistant to methicillin, strains that are resistant to one or more other ⁇ -lactam antibiotics, strains that are resistant to one or more fluoroquinolones and/or strains that are resistant to one or more other antibiotics (i.e. antibiotics other than ⁇ -lactams and fluoroquinolones).
  • a resistant strain is one in which the MIC of a given compound or class of compounds for that strain has shifted to a significantly higher number than for the parent (susceptible) strain.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram positive bacteria.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram positive bacteria which are resistant to one or more fluoroquinolone antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram negative bacteria.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram negative bacteria which are resistant to one or more fluoroquinolone antibiotics.
  • the compounds and formulations of the present invention can be used to treat or to prevent infections caused by bacterial strains associated with biowarfare. These may be strains which are category A pathogens as identified by the US government (e.g. those which cause anthrax, plague etc.) and/or they may be strains which are category B pathogens as identified by the US government (e.g. those which cause Glanders disease, mellioidosis etc).
  • the compounds and formulations of the present invention can be used to treat or to prevent infections caused by Gram positive bacterial strains associated with biowarfare (e.g. anthrax). More particularly, the compounds and formulations may be used to treat category A and/or category B pathogens as defined by the US government on 1 st Jan 2015.
  • the compounds of the invention may also be useful in treating other forms of infectious disease, e.g. fungal infections, parasitic infections and/or viral infections.
  • the compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the compounds of the invention may be administered in combination with other active compounds (e.g. antifungal compounds, oncology compounds) and, in particular, with other antibacterial compounds.
  • active compounds e.g. antifungal compounds, oncology compounds
  • the compound of the invention and the other active e.g. the other antibacterial compound
  • the compound of the invention and the other active e.g. the other antibacterial compound
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
  • the pharmaceutical compositions may be administered topically (e.g.
  • the skin in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders, suspensions, solutions or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories; or by inhalation (i.e. in the form of an aerosol or by nebulisation).
  • oral administration in the form of tablets, capsules, syrups, powders, suspensions, solutions or granules
  • parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories; or by inhalation (i.e. in the form of an
  • a compound with an in vitro MIC of, for example, 16-64 ⁇ g/mL may still provide an effective treatment against certain bacterial infections.
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in the art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.
  • the standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.
  • the present invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • the formulation may further comprise one or more other antibiotics, e.g. one or more fluoroquinolone antibiotics.
  • fluoroquinolone antibiotics include levofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, delafloxacin, zabofloxacin
  • a method of treating a bacterial infection comprising treating a subject in need thereof with a therapeutically effective amount of a compound of the invention.
  • Medical uses The compounds of the present invention can be used in the treatment of the human body.
  • the compounds of the invention may be for use in treating human bacterial infections such as infections of the genitourinary system, the respiratory tract, the gastrointestinal tract, the ear, the skin, the throat, soft tissue, bone and joints (including infections caused by Staphylococcus aureus).
  • the compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, mycobacterial infections (e.g. tuberculosis or leprosy), tonsillitis, Escherichia coli, prophylaxis before dental surgery, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, abdominal infection, bacteraemia, septicaemia, leprosy, sexually transmitted bacterial infection (e.g.
  • gonorrhoea Chlamydia
  • Neisseria infection e.g. gonorrhoea, meningitis
  • other fastidious Gram negative infection e.g. gonorrhoea, meningitis
  • bacterial vaginosis pelvic inflammatory disease
  • pseudomembranous colitis Helicobacter pylori
  • acute gingivitis Crohn's disease
  • rosacea fungating tumours, impetigo.
  • the compounds of the present invention may also be used in treating other conditions treatable by eliminating or reducing a bacterial infection. In this case they will act in a secondary manner alongside for example a chemotherapeutic agent used in the treatment of cancer.
  • a compound for use in the preparation of a medicament is provided.
  • the medicament may be for use in the treatment of any of the diseases, infections and indications mentioned in this specification.
  • a compound of the invention for medical use The compound may be used in the treatment of any of the diseases, infections and indications mentioned in this specification.
  • Veterinary uses They may be used in the treatment of the animal body.
  • the compounds of the present invention can be used to treat commercial animals such as livestock.
  • the livestock may be mammal (excluding humans) e.g. cows, pigs, goats, sheep, llamas, alpacas, camels and rabbits.
  • the livestock may be birds (e.g. chickens, turkeys, ducks, geese etc.).
  • the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.
  • the veterinary use may be to treat wild populations of animals in order to prevent the spread of disease to humans or to commercial animals.
  • the animals may be rats, badgers, deer, foxes, wolves, mice, kangaroos and monkeys and other apes.
  • a compound of the invention for veterinary use The compound may be used in the treatment of any of the animal diseases and infections and indications mentioned in this specification.
  • the present invention provides a veterinary formulation comprising a compound of the invention and a veterinarily acceptable excipient.
  • the methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant.
  • Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.
  • the formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal.
  • typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal.
  • the range is 0.1 to 10 mg per kg.
  • the veterinary practitioner, or the skilled person will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the compounds when treating animals the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed. Certain compounds of the invention may be used in the treatment of mastitis.
  • a particularly preferred method of administration is by injection into the udder of a subject (e.g. a cow, a goat, a pig or sheep).
  • a subject e.g. a cow, a goat, a pig or sheep.
  • the words“comprise” and “contain” and variations of the words, for example“comprising” and“comprises”, means “including but not limited to”, and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.
  • the singular encompasses the plural unless the context otherwise requires.
  • the indefinite article the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
  • Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
  • Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in“Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein. Throughout this specification these abbreviations have the following meanings:
  • DMSO dimethyl sulfoxide
  • HATU 1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate
  • HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate
  • NMP N-methylpyrrolidinone
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TMSCl trimethylsilyl chloride
  • TMSI trimethylsilyl iodide
  • TBTU N,N,N′,N′-Tetramethyl-O-(1H- benzotriazol-1-yl)uronium tetrafluoroborate
  • aldehyde (3) Reaction of pyridone (1) with commercially available 2-bromo-1,1-diethoxyethane (2), followed by hydrolysis of the acetal can generate aldehyde (3).
  • the alkylation reaction can be carried out in the presence of a base, such as Cs2CO3, in a solvent, such as dry NMP, at a temperature from 50-100 o C.
  • Hydrolysis can be effected using a strong acid, such as concentrated HCl, in a solvent, such as ACN, at room temperature.
  • Aldehyde (3) can be converted to ester (5) via reductive amination with the known amine (4), prepared as described in EP154142.
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • the ester group in (5) can be converted to the alcohol (6) using a reducing agent, such as LiAlH 4 or BHEt 3 + Li- (super hydride), in a solvent, such as THF, at a temperature from 0 o C to room temperature.
  • Allylation of alcohol (6) with allyl bromide in the presence of a base, such as NaH, in a solvent, such as THF or DMF, at a temperature from 0 o C to 60 o C, can furnish diene (7).
  • Addition of quaternary ammonium salts is optional.
  • RCM (ring controlled metathesis) of the diene (7) to macrocycle alkene (8) can be accomplished in the presence of Grubbs catalyst (first or second generation) in a suitable solvent, such as toluene, at a temperature from room temperature to 90 o C.
  • the RCM reaction may provide entirely the E isomer, entirely the Z isomer or a mixture thereof.
  • Deprotection of the cyclic ketal in (8) to release the ketone in (9) can be effected using acid catalysed conditions, such as use of a protic acid (10% HCl in a mixture of THF/H 2 O) or a Lewis acid (FeCl3 dispersed on silica).
  • Ketone (9) can be converted to amine (11) via reductive amination with amine (10).
  • the reaction can be performed using a borohydride reagent, such as sodium triacetoxyborohydride in a solvent, such as THF or 1,2- dichloroethane, at a temperature from room temperature to 80 o C. Addition of AcOH as a catalyst is optional.
  • Amine (11) can be converted to (13) (a subset of compounds of both formula (IV) and formula (VII)) under reductive amination conditions with aldehyde (12).
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2- dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • Amine (11) can be converted to (15) (another subset of compounds of both formula (IV) and formula (VII)) by coupling with (14), where LG represents a leaving group, such as a halide.
  • the reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K2CO3, with optional heating.
  • Scheme B The alkene double bond in ketone (9) in Scheme A can be hydrogenated to (16) by the action of H2 in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature.
  • Ketone (16) can then be transformed into (17) and (18) (two further subsets of compounds of formulae (IV) and (VII)) using an analogous series of transformations to those described in Scheme A for the conversion of ketone (9) to (13) and (15).
  • Certain compounds of formula (III) and (VII) can be made following Scheme A but using the ketal (19), prepared as described in US 6645980, in place of the amine (4).
  • Macrocycles (20) and (21) (two subsets of compounds of formulae (III) and (VII)) can be prepared using an analogous series of transformations to those described in Scheme A for the conversion of ester (5) to (13) and (15).
  • Ketal (24) can be formed by Scheme C from commercially available ketone (27) under Dean Stark conditions using ethylene glycol and catalytic p-TsOH (10%) in toluene.
  • Reductive ammination of aldehyde (3) (prepared as described in Scheme A) with commercially available hydroxy amine (30) can form alcohol (31).
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2- dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional. Allylation of alcohol (31) with allyl bromide in the presence of a base, such as NaH, in a solvent, such as THF or DMF, at a temperature from 0 o C to 60 o C, can furnish diene (32).
  • a base such as NaH
  • RCM ring closing metathesis of the diene (32) to macrocycle alkene (33)
  • RCM reaction may provide entirely the E isomer, entirely the Z isomer or a mixture thereof.
  • Deprotection of the nitrogen BOC protecting group in (33) can be performed under standard conditions, such as by the action of TFA in DCM at room temperature.
  • Amine (34) can be converted to (35) (a subset of compounds of both formula (VI) and formula (VII)) by reductive amination with aldehyde (12).
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • Amine (34) can be converted to (36) (another subset of compounds of both formula (VI) and formula (VII)) by coupling with (14), where LG represents a leaving group, such as a halide.
  • the reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K2CO3, with optional heating.
  • Amine (42) can be formed through reaction of commercially available bromo ester (40) with commercially available cyclic acetal protected amine (41).
  • the reaction can be performed in the presence of a base, such as K2CO3 or Et3N, in a solvent, such as ACN or DCM, at a temperature from 0 o C to room temperature.
  • Aldehyde (3) (prepared as described in Scheme A) can be converted to cyclic acetal (43) via reductive amination with the amine (42).
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • the ester group in cyclic acetal (43) can be converted to the alcohol (44) using a reducing agent, such as LiAlH4 or BHEt3 + Li- (super hydride), in a solvent, such as THF, at a temperature from 0 o C to room temperature.
  • Allylation of alcohol (44) with allyl bromide in the presence of a base, such as NaH, in a solvent, such as THF or DMF, at a temperature from 0 o C to 60 o C, can furnish diene (45).
  • a base such as NaH
  • a solvent such as THF or DMF
  • Addition of quaternary ammonium salts is optional.
  • RCM (ring controlled metathesis) of the diene (45) to macrocycle alkene (46) can be accomplished in the presence of Grubbs catalyst (first or second generation) in a suitable solvent, such as toluene, at a temperature from room temperature to 90 o C.
  • the RCM reaction may provide entirely the E isomer, entirely the Z isomer or a mixture thereof.
  • Deprotection of the cyclic acetal in (46) to release the aldehyde in (47) can be effected using acid catalysed conditions, such as use of a protic acid (10% HCl in a mixture of THF/H 2 O) or a Lewis acid (FeCl 3 dispersed on silica).
  • Aldehyde (47) can be converted to amine (48) via reductive amination with amine (10).
  • the reaction can be performed using a borohydride reagent, such as sodium triacetoxyborohydride in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of AcOH as a catalyst is optional.
  • Amine (48) can be converted to (49) (a subset of compounds of formula (V)) under reductive amination conditions with aldehyde (12).
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • Amine (48) can be converted to (50) (another subset of compounds of formula (V)) by coupling with (14), where LG represents a leaving group, such as a halide.
  • the reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K 2 CO 3 , with optional heating.
  • Certain other compounds of formula (V) can be made by Scheme G:
  • Scheme G The alkene double bond in amine (48) in Scheme G can be hydrogenated to (51) by the action of H 2 in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature.
  • Amine (51) can then be transformed into (52) and (53) (two further subsets of compounds of formula (V) using an analogous series of transformations to those described in Scheme F for the conversion of amine (48) to (49) and (50).
  • macrocycles (55) and (56) (a subset of compounds of formula (V)) can be prepared using an analogous series of transformation to those described in Scheme F for the conversion of aldehyde (3) to (49) and (50).
  • Aldehyde (54) can be formed by Scheme H from reaction of (1) with commercially available 3-bromo-1,1-dimethoxypropane (57), followed by hydrolysis of the acetal.
  • the alkylation reaction can be carried out in the presence of a base, such as Cs2CO3, in a solvent, such as dry NMP, at a temperature from 50-100 o C.
  • Hydrolysis of the acetal can be effected using a strong acid, such as concentrated HCl, in a solvent, such as ACN, at room temperature.
  • Reductive amination of aldehyde (3) (prepared as described in Scheme A) with amine (60) can form diene (61).
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • RCM (ring closing metathesis) of the diene (61) to macrocycle alkene (62) can be accomplished in the presence of Grubbs catalyst (first or second generation) in a suitable solvent, such as toluene, at a temperature from room temperature to 90 o C.
  • the RCM reaction may provide entirely the E isomer, entirely the Z isomer or a mixture thereof.
  • Deprotection of the nitrogen CBZ protecting group in (62) can be performed using base, such as KOH, in a solvent mixture of H 2 O and EtOH, at a temperature from 60 o C to reflux or refluxing in neat TFA or treatment with TMSI, in a solvent, such as DCM, at a temperature from room temperature to reflux.
  • Amine (63) can be converted to (64) (a subset of compounds of both formula (III) and formula (VII)) by reduction amination with aldehyde (12).
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • Amine (63) can be converted to (65) (another subset of compounds of both formula (III) and formula (VII)) by coupling with (14), where LG represents a leaving group, such as a halide.
  • the reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K2CO3, with optional heating.
  • Amine (60) can be formed by Scheme J:
  • Scheme K Hydrogenation of the alkene double bond and removal of nitrogen CBZ protecting in (62) in Scheme I to give amine (68) can be effected by the action of H 2 in the presence of a Pd/C catalyst in an alcoholic solvent, such as EtOH, at room temperature. Amine (68) can then be transformed into (69) and (70) (two further subsets of compounds of both formulae (III) and (VII)) using an analogous series of transformations to those described in Scheme I for the conversion of amine (63) to (64) and (65). Certain compounds of formulae (III) and (VII) can be made by Scheme L:
  • Scheme L Reaction of pyridone (71) with 2-bromo-1,1-diethoxyethane (2), followed by hydrolysis of the acetal can generate aldehyde (72).
  • the alkylation reaction can be carried out in the presence of a base, such as Cs 2 CO 3 , in a solvent, such as dry NMP, at a temperature from 50-100 o C.
  • Hydrolysis can be effected using a strong acid, such as concentrated HCl, in a solvent, such as ACN, at room temperature.
  • Aldehyde (72) can be converted to ester (73) via reductive amination with the known amine (19), prepared as described in US 6645980.
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • the ester group in (73) can be converted to the alcohol (74) using a reducing agent, such as LiAlH4 or BHEt3 + Li- (super hydride), in a solvent, such as THF, at a temperature from 0 o C to room temperature.
  • Alcohol (74) can be converted to azide (75) by a twostep process involving treatment with paraformaldehyde in the presence of TMSCl at room temperature, followed by treatment with an azide reagent, such as NaN 3 , in a solvent, such as THF, at room temperature, in the presence of 18-Crown-6.
  • a 3+2 cycloaddition of the azide onto the alkyne in (75) to deliver macrocycle alkene (76) can be accomplished using pentamethylcyclopentadienyl ruthenium chloride [Cp*RuCl] complexes in a suitable solvent, such as toluene or dioxane, at a temperature from room temperature to 60 o C.
  • Deprotection of the cyclic acetal in (76) to release the ketone in (77) can be effected using acid catalysed conditions, such as use of a protic acid (10% HCl in a mixture of THF/H2O) or a Lewis acid (FeCl3 dispersed on silica).
  • Ketone (77) can be converted to amine (78) via reductive amination with amine (10).
  • the reaction can be performed using a borohydride reagent, such as sodium triacetoxyborohydride in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of AcOH as a catalyst is optional.
  • Amine (78) can be converted to (79) (a subset of compounds of formulae (III) and (VII)) under reductive amination conditions with aldehyde (12).
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2- dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • Amine (78) can be converted to (80) (another subset of compounds of formulae (III) and (VII)) by coupling with (14), where LG represents a leaving group, such as a halide.
  • the reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K2CO3, with optional heating.
  • a base such as K2CO3, with optional heating.
  • macrocycles (81) and (82) (two further subsets of compounds of formulae (III) and (VII)) can be prepared.
  • the reaction can be carried out in a solvent, such as H 2 O or an alcohol, such as EtOH, at a temperature from room temperature to 80 o C.
  • Hydrolysis can be effected using a strong acid, such as concentrated HCl, in a solvent, such as ACN, at room temperature.
  • Aldehyde (99) can be converted to ester (100) via reductive amination with the known amine (19), prepared as described in US 6645980.
  • the reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2- dichloroethane, at a temperature from room temperature to 80 o C. Addition of 4 ⁇ sieves is optional.
  • the ester group in (100) can be converted to carboxylic acid (101) using base hydrolysis, such as Na2CO3 in a solvent mixture of H2O/EtOH, at a temperature from 50 o C to reflux or LiOH in a solvent mixture of H 2 O/THF, at a temperature from 50 o C to 80 o C or Et3N in H2O at a temperature from room temperature to 50 o C.
  • base hydrolysis such as Na2CO3 in a solvent mixture of H2O/EtOH
  • LiOH in a solvent mixture of H 2 O/THF
  • Et3N Et3N in H2O
  • Deprotection of the nitrogen CBZ group to give amine (102) can be achieved under standard conditions, such as use of H2 in the presence of Pd/C in an alcoholic solvent, such as EtOH, at room temperature.
  • Macrolactamisation of (102) can be effected under standard amide coupling conditions, such as HBTU, in the presence of a base, such as Et3N, in a solvent, such as DMSO, at room temperature.
  • Deprotection of the cyclic ketal in macrocycle (103) to release the ketone in (104) can be effected using acid catalysed conditions, such as use of a protic acid (10% HCl in a mixture of THF/H2O) or a Lewis acid (FeCl3 dispersed on silica).
  • Ketone (104) can be converted to amine (105) via reductive amination with amine (10).
  • the reaction can be performed using a borohydride reagent, such as sodium triacetoxyborohydride in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C. Addition of AcOH as a catalyst is optional. Amine (105) can be converted to (106) (a subset of compounds of both formula (III) and formula (VII)) under reductive amination conditions with aldehyde (12). The reaction can be performed using a borohydride reagent, such as tetramethylammonium triacetoxyborohydride or sodium triacetoxyborohydride, in a solvent, such as THF or 1,2-dichloroethane, at a temperature from room temperature to 80 o C.
  • a borohydride reagent such as sodium triacetoxyborohydride in a solvent, such as THF or 1,2-dichloroethane
  • Amine (105) can be converted to (107) (another subset of compounds of both formula (III) and formula (VII)) by coupling with (14), where LG represents a leaving group, such as a halide.
  • the reaction can be performed in a solvent, such as DMF or THF, in the presence of a base, such as K2CO3, with optional heating.
  • Experimental NMR spectra were obtained on a LC Bruker AV400 using a 5 mm QNP probe (Method A) or Bruker AV1500MHz with 5mm QNP probe and Z-axis gradients (Method B).
  • MS was carried out on a Waters Alliance ZQ MS (Methods A, B, C and D) using H 2 O and ACN mobile phase with pH modification as detailed under each method. Wavelengths were 254 and 210 nm.
  • Method A (Acidic pH) Column: YMC-Triart C1850 x 2 mm, 5 ⁇ m. Flow rate: 0.8 mL/min. Injection volume: 5 ⁇ L.
  • Mobile Phase A H2O B ACN C 50% H2O / 50% ACN + 1.0% formic acid
  • Method B (Acidic pH) Column: YMC Triart-C1850 x 2 mm, 5 ⁇ m Flow rate: 0.8 mL/min. Injection volume: 5 ⁇ L
  • Example 1 ( ⁇ ) trans-6-[( ⁇ 3-oxo-2H, 3H, 4H-pyrido[3,2-b][1,4]oxazin-6-yl ⁇ methyl)amino]- 8,13-dioxa-1,4-diazatetracyclo[12.6.2.14,7.017,21]tricosa-14(22),15,17 (21),18–tetraen-20- one (a) ( ⁇ ) tert-butyl trans-3-([(benzyloxy)carbonyl]amino)-4-hydroxy-pyrrolidine-1- carboxylate 1a
  • Example 3 ( ⁇ ) cis-6- ⁇ [( ⁇ 3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6- yl ⁇ methyl)amino]methyl ⁇ - 8,14-dioxa-1,4-diazatetracyclo[13.6.2.14,7.018,22]tetracosa-15 (23),16,18(22),19–tetraen-21-one
  • Example 4 7-[( ⁇ 3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl ⁇ methyl)amino]-14-oxa- 1,4,10-triazatetracyclo[13.6.2.14,8.018,22]tetracosa-15(23),16,18(22),19–tetraen-9,21- dione a) benzyl N- ⁇ 3-[(2-oxo-1,2-dihydroquinolin-7-yl)oxy]propyl ⁇ carbamate 4a
  • the aqueous was further extracted with DCM and the combined organics washed with brine and concentrated in vacuo to give a crude oil.
  • the oil was purified by flash chromatography using a gradient eluent system of 0-5% MeOH in DCM to give methyl 8- ⁇ 2-[7-(3- ⁇ [(benzyloxy)carbonyl]amino ⁇ propoxy)-2-oxo-1,2-dihydroquinolin-1-yl]ethyl ⁇ -1,4-dioxa-8- azaspiro[4.5]decane-6-carboxylate 4d (418 mg, 92 % yield) as a colourless oil.
  • reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO 3 , dried over Na 2 SO 4 and concentrated in vacuo.
  • the resulting residue was purified by flash column chromatography using a gradient eluent system of 0-20% MeOH in DCM/3N NH3 to give 7-[( ⁇ 3-oxo- 2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl ⁇ methyl)amino]-14-oxa-1,4,10- triazatetracyclo[13.6.2.1 4 , 8 .0 18 , 22 ]tetracosa-15(23),16,18(22),19–tetraen-9,21-dione 4 (14 mg, 70 % yield) as a yellow solid.
  • Example 8 (6S, 8S)-6- ⁇ [( ⁇ 3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6- yl ⁇ methyl)amino]methyl ⁇ -15-oxa-1,4,10-triazatetracyclo[14.6.2.04,8.019,23]tetracosa- 16,18,20,23-tetraene-9,22-dione (a) 1-tert-butyl 2-methyl (2S,4S)-4-( ⁇ [(benzyloxy)carbonyl]amino ⁇ methyl)pyrrolidine-1,2- dicarboxylate 8a
  • reaction mixture was then quenched with aqueous saturated ammonium chloride solution (50 mL) and extracted with Et2O (2 x 75 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo to give a yellow gum.
  • 9d 9e A stirred mixture of tert-butyl N-[2-(2-bromoethoxy)ethyl]carbamate (1.49 g, 5.55 mmol), ( ⁇ ) methyl 9-[2-(7-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)ethyl]-1,5-dioxa-9- azaspiro[5.5]undecane-7-carboxylate 9d (1.49 g, 3.70 mmol) and Cs 2 CO 3 (3.62 g, 11.11 mmol) in DMF (20 mL) was heated at 90 o C for 1 h. The reaction was allowed to cool to room temperature and diluted with H 2 O.
  • the resulting yellow gum was purified by flash column chromatography using a gradient eluent system of 50- 100% EtOAc in Et2O to give tert-butyl N-(3- ⁇ [2-oxo-1-(2-oxoethyl)-1,2-dihydroquinolin-7- yl]oxy ⁇ propyl)carbamate 10a (1.47 g, 41 % yield) as a clear gum.
  • the resulting yellow gum was purified by flash column chromatography using a gradient eluent system of 80-100% EtOAc in heptane to give methyl (2S,4S)-4-( ⁇ [(benzyloxy)carbonyl]amino ⁇ methyl)- 1- ⁇ 2-[7-(3- ⁇ [(tert-butoxy)carbonyl]amino ⁇ propoxy)-2-oxo-1,2-dihydroquinolin-1- yl]ethyl ⁇ pyrrolidine-2-carboxylate 10b (0.7 g, 27% yield) as a yellow gum.
  • reaction mixture was then flushed through a SCX cartridge and relevant fractions concentrated in vacuo to give a yellow gum, which was dissolved in DCM and treated with 3-oxo-2H,3H,4H-pyrido[3,2-b][1,4]oxazine-6- carbaldehyde (244 mg, 1.37 mmol).
  • the reaction mixture was stirred at room temperature for 1 h, before the addition of sodium triacetoxyborohydride (377 mg, 1.78 mmol) in one portion. After 5 min the reaction mixture was quenched with MeOH, concentrated to a low volume and purified using a SCX cartridge, eluting with MeOH/NH 3.
  • the broth dilution method involves a two-fold serial dilution of compounds in 96-well microtitre plates, giving a final concentration range of 0.03-64 ⁇ g/mL or 0.25-128 ⁇ g/mL.
  • Strains are grown in cation-adjusted Müller-Hinton broth (supplemented with 2% w/v NaCl in the case of methicillin-resistant S. aureus strains and 2% IsoVitalex in the case of Francisella tularensis) or on Müller-Hinton agar at 37°C in an ambient atmosphere.
  • the MIC is determined as the lowest concentration of compound that inhibits growth following an incubation period of 16-24 h, of 12-24 h (Bacillus anthracis), of 46-50 h (Francisella tularensis) or of 24-48 h (Yersinia pestis). Table 1 - MIC values against Gram-negative and Gram-positive bacterial strains
  • HepG2 ATCC HB-8065 Human hepatic cell line
  • HepG2 cells are seeded at 20,000 cells/well in 96-well microtitre plates in minimal essential medium (MEM) supplemented with a final concentration of 10% FBS and 1 mM sodium pyruvate.
  • MEM minimal essential medium
  • compound dilutions are prepared in Dulbecco’s minimum essential media (DMEM) supplemented with final concentrations of 0.001% FBS, 0.3% bovine albumin and 0.02% HEPES and added to cells.
  • DMEM minimum essential media
  • IC 50 (in ⁇ g/mL) of less than 1 is assigned the letter D; an IC 50 of from 1 to 10 is assigned the letter C; an IC 50 of from 10 to 100 is assigned the letter B; and an IC 50 of over 100 is assigned the letter A.

Abstract

Cette invention concerne des composés médicamenteux antibactériens contenant un système de cycle polycyclique comprenant un cycle macrocyclique, ainsi que des formulations pharmaceutiques desdits composés médicamenteux antibactériens. L'invention concerne également les utilisations de leurs dérivés dans le traitement des infections bactériennes et dans des méthodes de traitement des infections bactériennes. Des composés médicamenteux antibactériens capables de traiter des infections bactériennes qui sont actuellement difficiles à traiter à l'aide des composés médicamenteux existants sont en outre décrits.
PCT/GB2016/051514 2015-05-26 2016-05-25 Composés antibactériens WO2016189304A1 (fr)

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EP0154142A1 (fr) 1984-02-02 1985-09-11 Merck & Co. Inc. Hexahydroarylquinolizines substituées
WO2000047207A1 (fr) 1999-02-09 2000-08-17 Bristol-Myers Squibb Company Inhibiteurs lactame de fxa et methode
WO2003068790A2 (fr) * 2002-02-13 2003-08-21 Abbott Laboratories Composes antibacteriens a base de macrolides
US6645980B1 (en) 2000-05-25 2003-11-11 Sepracor Inc. Heterocyclic analgesic compounds and methods of use thereof
WO2006002047A2 (fr) 2004-06-15 2006-01-05 Glaxo Group Limited Agents antibacteriens
EP1900732A1 (fr) * 2005-06-24 2008-03-19 Toyama Chemical Co., Ltd. Nouveau composé hétérocyclique azoté et sel de celui-ci
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EP0154142A1 (fr) 1984-02-02 1985-09-11 Merck & Co. Inc. Hexahydroarylquinolizines substituées
WO2000047207A1 (fr) 1999-02-09 2000-08-17 Bristol-Myers Squibb Company Inhibiteurs lactame de fxa et methode
US6645980B1 (en) 2000-05-25 2003-11-11 Sepracor Inc. Heterocyclic analgesic compounds and methods of use thereof
WO2003068790A2 (fr) * 2002-02-13 2003-08-21 Abbott Laboratories Composes antibacteriens a base de macrolides
WO2006002047A2 (fr) 2004-06-15 2006-01-05 Glaxo Group Limited Agents antibacteriens
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EP1900732A1 (fr) * 2005-06-24 2008-03-19 Toyama Chemical Co., Ltd. Nouveau composé hétérocyclique azoté et sel de celui-ci
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