WO2004073709A1 - Antimicrobial agents - Google Patents

Antimicrobial agents Download PDF

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Publication number
WO2004073709A1
WO2004073709A1 PCT/GB2004/000621 GB2004000621W WO2004073709A1 WO 2004073709 A1 WO2004073709 A1 WO 2004073709A1 GB 2004000621 W GB2004000621 W GB 2004000621W WO 2004073709 A1 WO2004073709 A1 WO 2004073709A1
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WIPO (PCT)
Prior art keywords
alkyl
cyc
optionally substituted
radical
alk
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PCT/GB2004/000621
Other languages
French (fr)
Inventor
Lloyd Czaplewski
Jeffrey Errington
Dan BAYSTON
Andrew Boyd
Frederick Brookfield
Stuart Hatcher
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Prolysis Limited
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Publication of WO2004073709A1 publication Critical patent/WO2004073709A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • 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
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    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/16—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C279/28—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to the use of a class of tertiary amino compounds as antimicrobial agents, particularly as antibacterial or antifungal agents and to novel members of that class per se, and to pharmaceutical compositions comprising such compounds.
  • antibacterial agents including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol.
  • penicillins and cephalosporins including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol.
  • penicillins and cephalosporins tetracyclines
  • sulfonamides monobactams
  • fluoroquinolones and quinolones aminoglycosides
  • glycopeptides
  • MRSA methicillin resistant Staphylococcus aureus
  • MRCNS methicillin resistant coagulase negative Staphylococci
  • Penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.
  • Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin works by binding to the terminal D-AIa-D-Ala residues of the cell wall peptidoglycan precursor.
  • the high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin.
  • antifungal agents include amphotericin B, azoles and triazoles.
  • the fundamental mechanisms of action of these antifungal classes may vary but fungal resistance to these compounds is a growing problem.
  • resistant fungal pathogens such as Candida e.g. C. albicans, C. parapsilosis, C. krusei, C. glabrata and C. tropicalis; and Aspergillus e.g. A. fumigatus, A. terreus and A. niger, Cryptococcus e.g. C. neoformans;
  • This invention is based on the finding that certain tertiary amines have antimicrobial activity and makes available a new group of antimicrobial agents. It has been found that the compounds with which this invention is concerned are antibacterial with respect to a range of bacteria, of both the Gram-positive and Gram-negative types. Many of the compounds of the invention show activity against bacteria responsible for infections of the gastro-intestinal tract, such as Enterococci, and/or against those responsible for respiratory infections, such as Streptococcus pneumoniae and/or Haetnophilus influenzae, and/or those usually described as hospital acquired infections, such as Staphylococcus aureus and/or against yeasts responsible for fungal infections.
  • the present invention provides the use of a compound of formula (I) or a salt, hydrate or solvate thereof in the preparation of a composition for inhibiting microbial or plant growth:
  • L represents a divalent radical of formula (II)
  • Cyc 1 and Cyc 2 each independently represent an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms,
  • n, p, r, s, t and w each independently represent 0 or 1 , provided that at least one of m, n and p is 1 ,
  • R represents an optionally substituted C C ⁇ alkyl, C 2 -C 6 alkenyl, C- 2 -C 6 alkynyl, or Cyc-, (Cyc)-(C C 6 alkyl)-, (Cyc)-(C 2 -C6 alkenyl)-, or (Cyc)-(C 2 - C 6 alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms, and
  • R1 represents an optionally substituted (aryl)-(C ⁇ -C 6 alkyl)-, (aryl)-(C 2 -C 6 alkenyl)-(aryl)-(C 2 -C 6 alkynyl)-, (heteroaryl)-(CrC 6 alkyl)-, (heteroaryl)-(C 2 - C 6 alkenyl)- or (heteroaryl)-(C 2 -C6 alkynyl)- radical.
  • L represents a divalent radical of formula (III)
  • Alk i Alk i
  • Alk 2 each independently represent an optionally substituted divalent CrC 3 alkylene radical
  • Cyc 1 represents an optionally substituted divalent monocyclic carbocyclic radical having from 5 to 8 ring atoms
  • n, p each independently represent 0 or 1, provided that at least one of m, n and p is 1 ,
  • R represents an optionally substituted C ⁇ -C 6 alkyl, cycloalkyl(CrC 6 alkyl)- or phenyl (CrC 6 alkyl)- group and
  • Ri represents an optionally substituted phenyl(CrC ⁇ alkyl)- group.
  • the invention provides a method for the treatment of microbial (particularly bacterial or fungal) infections in humans and non-human animals e.g. other mammals, birds and fish, which comprises administering to a subject suffering such infection an antimicrobially effective dose of a compound of formula (I) as defined above.
  • Antimicrobial compositions of the invention may additionally include an antimicrobial agent other than one defined by reference to formula (I) above.
  • microbe is to be understood as referring to bacterial or fungal microorganisms.
  • (CrC 6 )alkyl means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
  • divalent (d-C 6 )alkylene radical means a saturated hydrocarbon chain having from 1 to 6 carbon atoms and two unsatisfied valences.
  • (C2-C 6 )alkenyl means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or 2 stereochemistry where applicable.
  • the term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
  • divalent (C 2 -C 6 )alkenylene radical means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one double bond, and two unsatisfied valences.
  • C 2 -C 6 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl.
  • divalent (C 2 -C ⁇ )alkynylene radical means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one triple bond, and two unsatisfied valences.
  • cycloalkyl refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyl refers to a carbocyclic radical having from 3-8 carbon atoms containing at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • aryl refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.
  • Carbocyclic refers to a cyclic radical whose ring atoms are all carbon, and includes aryl, cycloalkyl and cycloalkenyl radicals.
  • heteroaryl refers to an aromatic radical containing one or more heteroatoms selected from S, N and O.
  • Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyi, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
  • heterocyclyl or “heterocyclic” includes “heteroaryl” as defined above, and in particular means a non-aromatic radical containing one or more heteroatoms selected from S, N and O.
  • radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyi, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
  • lipophilic as used herein in relation to a substituent means that it has a positive substituent hydrophobicity constant ( ⁇ ).
  • ⁇ hydrophobicity constant
  • substituted as applied to any moiety herein means substituted with at least one substituent , for example selected from (CrC 6 )alkyl, (CrC 6 )alkoxy, hydroxy, hydroxy(Cr C 6 )alkyl, mercapto, mercapto(C ⁇ -C 6 )alkyl, (C-i-CeJalkylthio, halo (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, nitro, nitrile (-CN), oxo, phenyl, -COOH, -COOR A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A , -SO 2 NHR A , -CONR A R B , -SO 2 NR A R B ,
  • (CrC 6 )alkyl halo, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, and phenyl and those most commonly regarded as lipophilic.
  • Other substituents listed which contain alkyl groups may be lipophilic depending on the particular alkyl groups present.
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like.
  • Those compounds (I) which are basic can form salts, including pharmaceutically or veterinarily acceptable salts with inorganic acids, e.g.
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic and p-toluene sulphonic acids and the like.
  • Some compounds of the invention contain one or more actual or potential chiral centres because of the presence of asymmetric carbon atoms.
  • the presence of several asymmetric carbon atoms gives rise to a number of diastereoisomers with R or S stereochemistry at each chiral centre.
  • the invention includes all such diastereoisomers and mixtures thereof.
  • R2 and R 3 form a ring together with the nitrogen atoms to which they are attached, that ring may be a monocyclic 5 or 6 membered ring.
  • Radicals L have the structure (II) as defined above.
  • p may be 1 while w may be 1 or 0.
  • Cyc 1 and/or Cyc 2 each may be a cycloalkyl ring of from 5 to 7, preferably 6 ring carbons, or a phenyl ring, and Alk 1 , Alk 2 , Alk 3 and Alk 4 , when present, may each independently represent -CH 2 - or -CH 2 CH 2 -.
  • w may be 0, m, p and n may be 1 , Alk 1 and Alk 2 may be -CH 2 -, and Cyc 1 may be 1 ,4-phenylene or 1 ,4- cyclohexylene.
  • R1 represents an optionally substituted (aryl)-(CrC 6 alkyl)-, (aryI)-(C 2 -C 6 alkenyl)- (aryl)-(C 2 -C 6 alkynyl)-, (heteroaryl)-(C- ⁇ -C 6 alkyl)-, (heteroaryl)-(C 2 -C 6 alkenyl)- or (heteroaryl)-(C 2 -C 6 alkynyl)- radical.
  • Optionally substituted heteroaryl groups which may be present in R 1 include optionally substituted 2- and 3-thienyl, 2- and 3-furanyl, and 2-, 3- and 4-pyridyl .
  • Optionally substituted aryl groups which may be present in R 1 include optionally substituted phenyl, and naphthyl, the former being preferred.
  • Optional substituents which may be present in R 1 include chloro, bromo, iodo, nitro, cyano, trifuoromethyl, C C ⁇ alkyl, CrC 6 alkoxy, C 1 -C- 6 alkylthio, C C ⁇ alkylsulfonyl, phenylsulfonyl and methylenedioxy.halo such as chloro, bromo and iodo, nitro, cyano, trifuoromethyl, CrC 6 alkyl such as methyl ethyl and t-butyl, and C C ⁇ alkoxy such as methoxy and ethoxy.
  • substituents present in R 1 be lipophilic rather than hydrophilic.
  • R 1 is benzyl, phenylethyl or phenylpropyl, optionally substituted in the phenyl ring by at least one lipophilic substituent as discussed above.
  • R represents an optionally substituted C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or (Cyc)-(C C ⁇ alkyl)-, (Cyc)-(C 2 -C 6 alkenyl)-, or (Cyc)-(C 2 -C 6 alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms. Cyc when present may be cycloalkyl, cycloalkenyl, aryl or aromatic or non-aromatic heterocyclic.
  • Cyc groups include cyclopentyl, cyclohexyl, cyclohexyl, phenyl, 2-, 3- and 4-pyridyl, 2-, 3- and 4- piperidinyl, 2- and 3-thienyl and 2- and 3-furanyl.
  • R groups include optionally substituted methyl, ethyl, n- and sec-propyl, n-, sec- and t-butyl, straight and branched chain pentyl and hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclopentylmethyl, cycloheptylmethyl, 2-, 3- and 4-pyridyl methyl, 2- and 3- furanylmethyl, 2 and 3-thienylmethyl, 2-, 3- and 4-piperidinylmethyl, and 2- and 3- morpholinylmethyl.
  • R groups are is methyl, ethyl, n- or sec- propyl, n-, sec- or t-butyl, or phenyl or benzyl, optionally substituted in the phenyl ring by chloro, bromo or iodo, nitro, cyano, trifuoromethyl, methyl, ethyl, t-butyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl or phenylsulfonyl.
  • the starting compound (I) wherein B is -NH 2 may be prepared from an N-protected diamino compound Pr-NH-L-NH 2 wherein L has the same meaning as in formula (I), and Pr is an N-protecting group, by reductive alkylation of the free amino group, followed by removal of the protecting group.
  • the protecting group Pr may be a support resin such as Wang resin.
  • the compounds with which the invention are concerned are antimicrobially active, and may therefore be of use in the treatment of microbial infection in humans and non-human animals e.g. other mammals, birds and fish.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Optimum dose levels and frequency of dosing will be determined by clinical trial.
  • the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
  • the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
  • Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the compounds with which the invention are concerned inhibit plant growth, and may therefore be of use as herbicides.
  • the compounds may be formulated for spraying as a solution or suspension, as a powder for dusting, or as a thickened solution or suspension for painting onto the plant.
  • the specific dose level for inhibition of plant growth may depend on plant species and/ or the stage of the plant's growth cycle. Optimum dose levels and frequency of dosing will be determined by laboratory and/or field trial.
  • Step 1 Loading of diamine onto PNP-Wang resin
  • Step 2a Double reductive alkylation to give a symmetric tertiary amine
  • Step l W-[(4- ⁇ [di(4-chlorobenzyl)amino]methyl ⁇ -cyclohexyl)-methyl]-amino cyanoiminophenoxide
  • Diastereomer B HPLC-MS: m/z 433 [M+H] + .
  • the analytical methods used to characterise compounds comprised HPLC-MS and 1 H and 3 C NMR.
  • HPLC-MS instrument comprises:
  • Hewlett Packard 1314A variable wavelength detector (set at 215nm) Gilson 215 autosampler fitted with a 1ml syringe Polymer Labs PL1000 Evaporative Light Scattering Detector (where fitted)
  • Micromass ZMD mass spectrometer operating in Electrospray positive ionisation mode.
  • the LC eluent is split, after flowing through the VWD uv detector, and approximately 200 ⁇ l/min enters the mass spectrometer, 800 ⁇ l/min to the ELS (where fitted).
  • the instruments were controlled using Micromass MassLynx 3.5 software under Windows NT4.0
  • Bacillus subtilis 168CA Bacillus subtilis 168CA.
  • Candida albicans ATCC 90028 Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Haemophilus influenzae ATCC 49247, Pseudomonas aeruginosa 101021 , Saccharomyces cerevisiae MYA-658, Staphylococcus aureus MS 601055 and Streptococcus pneumoniae ATCC 49619.
  • Microtitre plates containing the test compounds were inoculated with a starting inoculum of 5x10 5 cfu/ml.
  • Mueller-Hinton broth (Oxoid) was used for all non-fastidious organisms.
  • S. pneumoniae and H. influenzae were grown in brain heart infusion (Sigma) supplemented with 5% horse serum and 2 mg of NAD per litre (/-/. influenzae).
  • the MIC was defined as the lowest concentration of compound inhibiting visible growth.
  • test compounds For S. cerevisiae and C. albicans, Sabouraud dextrose broth (Sigma) was used. Microtitre plates containing the test compounds were inoculated with 1 :100 dilutions of cultures at an absorbance at 600 nm (A 6 oo) of 0.09. S. cerevisiae and C. albicans were incubated at 30°C for 44-48 h and at 37°C for 28 h, respectively. The MIC was defined as the lowest concentration of compound inhibiting visible growth. The IC50 was defined as a reduction in A ⁇ oo of >50% compared to A 6 oo of a culture grown in the absence of compound.
  • Activities were scored as 'A' if the MIC was single digit eg. 8 microgrammes/ml, 'B' if the MIC was 16 to 64 microgrammes/ml and 'C if the MIC was greater than 64 microgammes/ml.
  • the data set in the above table is data collected from B. subtilis, E. coli and S. cerevisiae tests. IC 50 values were used to evaluate effects of compounds on the growth of yeast.

Abstract

Compounds of formula (I) are antibacterial agents: wherein B represents R2R3N-, R2NH-C(=NR3)-, or R2NH-C(=NR3)-NR4- wherein each of R2, R3 and R4 represents hydrogen or a C1-C6 alkyl, phenyl, phenyl(C1-C6 alkyl)-, monocyclic heteroaryl, monocyclic heteroaryl (C1-C6 alkyl)-, or cyano group, or R2 and R3 form a ring together with the nitrogen atoms to which they are attached; L represents a divalent radical of formula (II): -(Alk1)m-(CYC1)p (Alk2)n-[(Alk3)r(CyC2)s-(Alk4)t]w-, wherein Alk1, Alk2, Alk3and Alk4 each independently represent (i) an optionally substituted divalent C1-C3 alkylene radical which may optionally contain an ether (-0-), thioether (-S-) or amino (-NR A- ) link wherein RA is hydrogen or C1-C3 alkyl, (ii) an optionally substituted -CH=CH- radical, or (iii) a -C=C- radical; Cyc1 and Cyc2 each independently represent an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms; m, n, p, r, s, t and w each independently represent 0 or 1, provided that at least one of m, n and p is 1; R represents an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Cyc-, (Cyc)-(C1-C6 alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2-C6 alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms; and R1 represents an optionally substituted (aryl)-(C1-C6 alkyl)-, (aryl)-(C2-C6 alkenyl)-(aryl)-(C2-C6 alkynyl)-, (heteroaryl)-(C1-C6 alkyl)-, (heteroaryl)-(C2-C6 alkenyl)- or (heteroaryl)-(C2-C6 alkynyl)- radical.

Description

Antimicrobial Agents
This invention relates to the use of a class of tertiary amino compounds as antimicrobial agents, particularly as antibacterial or antifungal agents and to novel members of that class per se, and to pharmaceutical compositions comprising such compounds.
Background to the Invention
Many classes of antibacterial agents are known, including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundamental mechanisms of action of these antibacterial classes vary.
Bacterial resistance to many known antibacterials is a growing problem. Accordingly there is a continuing need in the art for alternative antibacterial agents, especially those that have mechanisms of action fundamentally different from the known classes.
Amongst the Gram-positive pathogens, such as Staphylococci, Streptococci, Mycobacteria and Enterococci, resistant strains have evolved/arisen which makes them particularly difficult to eradicate. Examples of such strains are methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase negative Staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.
Recently there has been an emergence of vancomycin-resistant strains of enterococci (Woodford N., 1998. Glycopeptide-resistant enterococci: a decade of experience. Journal of Medical Microbiology. 47: 849-62). Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin works by binding to the terminal D-AIa-D-Ala residues of the cell wall peptidoglycan precursor. The high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin.
In view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing number of resistant bacteria, particularly the vancomycin resistant enterococci and beta-lactam antibiotic-resistant bacteria, such as methicillin- resistant Staphylococcus aureus, is of utmost importance.
Many classes of antifungal agents are known, including amphotericin B, azoles and triazoles. The fundamental mechanisms of action of these antifungal classes may vary but fungal resistance to these compounds is a growing problem. There is an increased awareness of the morbidity and mortality associated with infections by resistant fungal pathogens such as Candida e.g. C. albicans, C. parapsilosis, C. krusei, C. glabrata and C. tropicalis; and Aspergillus e.g. A. fumigatus, A. terreus and A. niger, Cryptococcus e.g. C. neoformans;
Scedosporium e.g. S. prolificans, and Fusarium species (Canuto et. al. 2002. Antifungal drug resistance to azoles and polyenes. Lancet Infection and Disease
2; 550-563). Accordingly, there is a continuing need in the art for alternative antifungal agents, especially those that have mechanisms of action fundamentally different from the known classes.
Brief Description of the Invention
This invention is based on the finding that certain tertiary amines have antimicrobial activity and makes available a new group of antimicrobial agents. It has been found that the compounds with which this invention is concerned are antibacterial with respect to a range of bacteria, of both the Gram-positive and Gram-negative types. Many of the compounds of the invention show activity against bacteria responsible for infections of the gastro-intestinal tract, such as Enterococci, and/or against those responsible for respiratory infections, such as Streptococcus pneumoniae and/or Haetnophilus influenzae, and/or those usually described as hospital acquired infections, such as Staphylococcus aureus and/or against yeasts responsible for fungal infections.
While the mechanism of action of the compounds with which the invention is concerned may be of some interest, it is their overall antimicrobial effect which makes them useful, and the invention is therefore not limited by any theory of their action.
Detailed Description of the Invention
In a broad aspect, the present invention provides the use of a compound of formula (I) or a salt, hydrate or solvate thereof in the preparation of a composition for inhibiting microbial or plant growth:
Figure imgf000004_0001
wherein
B represents R2R3N-, R2NH-C(=NR3)-, or R2NH-C(=NR3)-NR4- wherein each of R2, R3 and R4 represents hydrogen or a C C6 alkyl, phenyl, phenyl(CrC6 alkyl)-, monocyclic heteroaryl, monocyclic heteroaryl(CrC6 alkyl)-, or cyano group, or R2 and R3 form a ring together with the nitrogen atoms to which they are attached,
L represents a divalent radical of formula (II)
-(Alki)m-(Cyci)p-(Alk2)n-[(Alk3)r-(Cyc2)s-(Alk4)t]w- (II)
wherein Alk1, Alk2, Alk3 and Alk4 each independently represent (i) an optionally substituted divalent Cι-C3 alkylene radical which may optionally contain an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or C-1-C3 alkyl, (ii) an optionally substituted -CH=CH- radical, or (iii) a -C≡C- radical,
Cyc1 and Cyc2 each independently represent an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms,
m, n, p, r, s, t and w each independently represent 0 or 1 , provided that at least one of m, n and p is 1 ,
R represents an optionally substituted C Cβ alkyl, C2-C6 alkenyl, C-2-C6 alkynyl, or Cyc-, (Cyc)-(C C6 alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2- C6 alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms, and
R1 represents an optionally substituted (aryl)-(Cι-C6 alkyl)-, (aryl)-(C2-C6 alkenyl)-(aryl)-(C2-C6 alkynyl)-, (heteroaryl)-(CrC6 alkyl)-, (heteroaryl)-(C2- C6 alkenyl)- or (heteroaryl)-(C2-C6 alkynyl)- radical.
rrower aspect of the invention, in the compounds (I):
B represents NH2-, CH3NH-, NH2-C(=NH)-, NH2-C(=NH)-NH- N=C-NH2-C(=NH)-NH- or ;
Figure imgf000005_0001
L represents a divalent radical of formula (III)
-(Alki)m-(CycV(Alk2)n- (HI) wherein Alk , and Alk2 each independently represent an optionally substituted divalent CrC3 alkylene radical,
Cyc1 represents an optionally substituted divalent monocyclic carbocyclic radical having from 5 to 8 ring atoms,
m, n and p each independently represent 0 or 1, provided that at least one of m, n and p is 1 ,
R represents an optionally substituted Cι-C6 alkyl, cycloalkyl(CrC6 alkyl)- or phenyl (CrC6 alkyl)- group and
Ri represents an optionally substituted phenyl(CrCβ alkyl)- group.
The invention also includes compounds of formula (I) defined above wherein B is R2NH-C(=NR3)-, or R2NH-C(=NR3)-NR4-, and of course the salts, hydrates and solvates thereof. In particular, the invention includes compounds of formula (I) defined above in relation to the broad, intermediate and narrower aspects of the invention, wherein B represents CH3NH-, NH2-C(=NH)-, NH2-C(=NH)-NH-, N≡C-NH2-C(=NH)-NH- or
Figure imgf000006_0001
and salts, hydrates and solvates thereof.
In another aspect, the invention provides a method for the treatment of microbial (particularly bacterial or fungal) infections in humans and non-human animals e.g. other mammals, birds and fish, which comprises administering to a subject suffering such infection an antimicrobially effective dose of a compound of formula (I) as defined above.
In a further aspect of the invention there is provided a method for the treatment of microbial (particularly bacterial or fungal) contamination by applying an antimicrobially effective amount of a compound of formula (I) as defined above to the site of contamination.
In a further aspect of the invention there is provided an antimicrobial pharmaceutical or veterinary composition comprising a compound as defined by reference to formula (I) above particularly one wherein B represents NH2- C(=NH)- or NH2-C(=NH)-NH-, and salts, hydrates and solvates thereof, together with a pharmaceutically or veterinarily acceptable excipient or carrier.
Antimicrobial compositions of the invention may additionally include an antimicrobial agent other than one defined by reference to formula (I) above.
As used herein the term "microbe" is to be understood as referring to bacterial or fungal microorganisms.
As used herein the term "(CrC6)alkyl" means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
As used herein the term "divalent (d-C6)alkylene radical" means a saturated hydrocarbon chain having from 1 to 6 carbon atoms and two unsatisfied valences.
As used herein the term "(C2-C6)alkenyl" means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or 2 stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
As used herein the term "divalent (C2-C6)alkenylene radical" means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one double bond, and two unsatisfied valences.
As used herein the term "C2-C6 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl.
As used herein the term "divalent (C2-Cβ)alkynylene radical" means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one triple bond, and two unsatisfied valences.
As used herein the term "cycloalkyl" refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein the term "cycloalkenyl" refers to a carbocyclic radical having from 3-8 carbon atoms containing at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
As used herein the term "aryl" refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.
As used herein the term "carbocyclic" refers to a cyclic radical whose ring atoms are all carbon, and includes aryl, cycloalkyl and cycloalkenyl radicals. As used herein the term "heteroaryl" refers to an aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyi, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
As used herein the unqualified term "heterocyclyl" or "heterocyclic" includes "heteroaryl" as defined above, and in particular means a non-aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyi, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
The term "lipophilic" as used herein in relation to a substituent means that it has a positive substituent hydrophobicity constant (π). (A positive value for π indicates that the substituent is more lipophilic than hydrogen, whereas a negative value indicates it is less lipophilic, i.e. more hydrophilic, than hydrogen).
Unless otherwise specified in the context in which it occurs, the term "substituted" as applied to any moiety herein means substituted with at least one substituent , for example selected from (CrC6)alkyl, (CrC6)alkoxy, hydroxy, hydroxy(Cr C6)alkyl, mercapto, mercapto(Cι-C6)alkyl, (C-i-CeJalkylthio, halo (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, nitro, nitrile (-CN), oxo, phenyl, -COOH, -COORA, -CORA, -SO2RA, -CONH2, -SO2NH2, -CONHRA, -SO2NHRA, -CONRARB, -SO2NRARB, -NH2, -NHRA, -NRARB, -OCONH2, -OCONHRA , -OCONRARB, -NHCORA, -NHCOORA, -NRBCOORA, -NHSO2ORA, -NRBSO2ORA, -NHCONH2, -NRACONH2, -NHCONHR8 -NRACONHRB, -NHCONRARB or -NRACONRARB wherein RA and RB are independently a (C C6)alkyl group. Of the above substituents, (CrC6)alkyl, halo, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, and phenyl and those most commonly regarded as lipophilic. Other substituents listed which contain alkyl groups may be lipophilic depending on the particular alkyl groups present.
As used herein the term "salt" includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like. Those compounds (I) which are basic can form salts, including pharmaceutically or veterinarily acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic and p-toluene sulphonic acids and the like.
Some compounds of the invention contain one or more actual or potential chiral centres because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such diastereoisomers and mixtures thereof.
The group B
B represents R2R3N-, R2NH-C(=NR3)-, or R2NH -C(=NR3)-NR4- wherein each of R2, R3 and R4 represents hydrogen or a CrC6 alkyl, phenyl, phenyl(CrC6 alkyl)- or cyano group, or R2 and R3 form a ring together with the nitrogen atoms to which they are attached, Examples of R2, R3 and R groups other than hydrogen include methyl and benzyl. B may be an amino group NH2-, but is more preferably an amidino -NH2-C(=NH)-, or guanidino group NH2-C(=NH)-NH-. When R2 and R3 form a ring together with the nitrogen atoms to which they are attached, that ring may be a monocyclic 5 or 6 membered ring.
The radical L
This radical separates a nitrogen atom in B and the nitrogen of the substructure -NRRι. Radicals L have the structure (II) as defined above. In one class of structures (II) p may be 1 while w may be 1 or 0. When present Cyc1 and/or Cyc2 each may be a cycloalkyl ring of from 5 to 7, preferably 6 ring carbons, or a phenyl ring, and Alk1, Alk2, Alk3 and Alk4, when present, may each independently represent -CH2- or -CH2CH2-. For example, w may be 0, m, p and n may be 1 , Alk1 and Alk2 may be -CH2-, and Cyc1 may be 1 ,4-phenylene or 1 ,4- cyclohexylene.
Figure imgf000011_0001
R1 represents an optionally substituted (aryl)-(CrC6 alkyl)-, (aryI)-(C2-C6 alkenyl)- (aryl)-(C2-C6 alkynyl)-, (heteroaryl)-(C-ι-C6 alkyl)-, (heteroaryl)-(C2-C6 alkenyl)- or (heteroaryl)-(C2-C6 alkynyl)- radical. Optionally substituted heteroaryl groups which may be present in R1 include optionally substituted 2- and 3-thienyl, 2- and 3-furanyl, and 2-, 3- and 4-pyridyl . Optionally substituted aryl groups which may be present in R1 include optionally substituted phenyl, and naphthyl, the former being preferred. The optionally substituted CrC6 alkylene, C2-C6 alkenylene and C2-C6 alkynylene radicals part of R1 may be straight or branched chain and include -CH2-, -CH2CH2-, -CH2CH=CH- and -CH2C≡CCH2. Optional substituents which may be present in R1 include chloro, bromo, iodo, nitro, cyano, trifuoromethyl, C Cβ alkyl, CrC6 alkoxy, C1-C-6 alkylthio, C Cβ alkylsulfonyl, phenylsulfonyl and methylenedioxy.halo such as chloro, bromo and iodo, nitro, cyano, trifuoromethyl, CrC6 alkyl such as methyl ethyl and t-butyl, and C Cβ alkoxy such as methoxy and ethoxy. At present it is preferred that substituents present in R1 be lipophilic rather than hydrophilic. At present it is preferred that R1 is benzyl, phenylethyl or phenylpropyl, optionally substituted in the phenyl ring by at least one lipophilic substituent as discussed above.
The group R
R represents an optionally substituted Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or (Cyc)-(C Cβ alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2-C6 alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms. Cyc when present may be cycloalkyl, cycloalkenyl, aryl or aromatic or non-aromatic heterocyclic. Examples of Cyc groups include cyclopentyl, cyclohexyl, cyclohexyl, phenyl, 2-, 3- and 4-pyridyl, 2-, 3- and 4- piperidinyl, 2- and 3-thienyl and 2- and 3-furanyl. Examples of CrC6 alkyl, C2-C6 alkenyl and C2-Cβ alkynyl radicals which may be present in R may be straight or branched chain, and include methyl, ethyl, n- and sec-propyl, n-, sec- and t-butyl, CH3CH=CH- and CH3C≡CCH2. Any optionally substituted C C6 alkylene, C2-C6 alkenylene and C2-Cβ alkynylene radicals part of R may be straight or branched chain and include optionally substituted -CH2-, -CH2CH2-, -CH2CH=CH- and - CH2C=CCH2.
Specific examples of R groups include optionally substituted methyl, ethyl, n- and sec-propyl, n-, sec- and t-butyl, straight and branched chain pentyl and hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclopentylmethyl, cycloheptylmethyl, 2-, 3- and 4-pyridyl methyl, 2- and 3- furanylmethyl, 2 and 3-thienylmethyl, 2-, 3- and 4-piperidinylmethyl, and 2- and 3- morpholinylmethyl. Currently preferred R groups are is methyl, ethyl, n- or sec- propyl, n-, sec- or t-butyl, or phenyl or benzyl, optionally substituted in the phenyl ring by chloro, bromo or iodo, nitro, cyano, trifuoromethyl, methyl, ethyl, t-butyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl or phenylsulfonyl.
Specific compounds with which the invention is concerned include those of the Examples herein. Compounds of the invention may be prepared by literature methods, for example methods analogous to those used in the Examples herein. For example compounds (I) wherein B is R2NH- may be prepared by alkylation of the corresponding compound wherein B is -NH2.
Compounds (I) wherein B is amidino (NH2-C(=NH)-) may be prepared from the corresponding compound wherein B is nitrile, by reaction with the reaction product of ammonium chloride and trimethyl aluminium. The resultant amidino compound may then be substituted on the amidino nitrogens as desired to form compounds (I) wherein R and/or R3 are other than hydrogen.
Compounds (I) wherein B is guanidino (NH2-C(=NH)-NH-) may be prepared from the corresponding compound wherein B is -NH2, by reaction with diisopropylethylamine and 1 -H-pyrazole-1 -carboxamidine hydrochloride. The resultant guanidino compound may then be substituted on the guanidino nitrogens as desired to form compounds (I) wherein R2 and/or R3 and/or R are other than hydrogen.
In each of the above cases, the starting compound (I) wherein B is -NH2 may be prepared from an N-protected diamino compound Pr-NH-L-NH2 wherein L has the same meaning as in formula (I), and Pr is an N-protecting group, by reductive alkylation of the free amino group, followed by removal of the protecting group. In a special instance of this synthesis, the protecting group Pr may be a support resin such as Wang resin.
As mentioned above, the compounds with which the invention are concerned are antimicrobially active, and may therefore be of use in the treatment of microbial infection in humans and non-human animals e.g. other mammals, birds and fish. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Optimum dose levels and frequency of dosing will be determined by clinical trial.
The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
For topical application to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
Also as mentioned above, the compounds with which the invention are concerned inhibit plant growth, and may therefore be of use as herbicides. For such uses the compounds may be formulated for spraying as a solution or suspension, as a powder for dusting, or as a thickened solution or suspension for painting onto the plant. It will be understood that the specific dose level for inhibition of plant growth may depend on plant species and/ or the stage of the plant's growth cycle. Optimum dose levels and frequency of dosing will be determined by laboratory and/or field trial.
The following Examples describe the preparation of illustrative compounds (I) for use according to the present invention, and the antibacterial and antifungal properties thereof: A. Typical Primary Amine Synthesis
Step 1 Loading of diamine onto PNP-Wang resin
Figure imgf000016_0001
To a round bottomed flask containing 4-nitrophenoxy carbonyl Wang resin (3g, 3.9mmol) and DMF (30ml) was added 1 ,4-cyclohexane bis(methylamine) (5.54g, 39mmol, 10eq). The mixture was agitated for 72 hrs and the resin collected by filtration. The resin was washed with [DMF (3 x 50ml), MeOH (3 x 50ml)] x 3; [DCM (3 x 50ml), MeOH (3 x 50ml)] x 3; 50ml CH2CI2 and TBME (3 x 50ml) and dried in the vacuum oven overnight. To check that the reaction was complete 0.01 g of resin was cleaved (1ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: m/z 143 [M+H]+.
Step 2a Double reductive alkylation to give a symmetric tertiary amine
Figure imgf000016_0002
To a round bottomed flask containing the resin from step 1 (10g, 13mmol) in DMF (100ml) was added 4-f-butyl benzaldehyde (21 g, 130mmol, 10eq) and acetic acid (7.8g, 130mmol, 10eq). After shaking for 30 mins sodium triacetoxyborohydride (27.5g, 130mmol, 10eq) was added and the resulting mixture agitated for 20 hrs. The resin was then collected by filtration and washed with [DMF (3 x 100ml), MeOH (3 x 100ml)] x 3; [DCM (3 x 100ml), MeOH (3 x 100ml)] x 3; 100ml CH2CI2 and TBME (3 x 100ml) and dried in the vacuum oven overnight. To check that the reaction was complete 0.01 g of resin was cleaved (1 ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: m/z 436 [M+H]+.
Step 2b Reductive alkylation
Figure imgf000017_0001
To a round bottomed flask containing the resin from step 1 (13g, 13mmol) was added a solution of acetic acid/DMF (1:100, 100ml) and the resultant suspension agitated for 10 mins. Cyclohexanecarboxaldehyde (7.28g, 65mmol, 5eq) was added and the mixture agitated for 20 hrs. The resin was washed with DMF (5 x 100ml) and CH2CI2 (5 x 100ml) (care was taken to keep the resin moist during the wash cycles), re-swollen in DMF (100ml) and sodium triacetoxyborohydride (13.78g, 65mmol, 5eq) added. The mixture was agitated for a further 20 hrs and the resin then collected by filtration and washed with [DMF (3 x 100ml), MeOH (3 x 100ml)] x 3; [DCM (3 x 100ml), MeOH (3 x 100ml)] x 3; 100mi CH2CI2 and TBME (3 x 100ml) and dried in the vacuum oven overnight. To check that the reaction was complete 0.01 g of resin was treated with excess benzoyl chloride in CH2CI2 for 1 hour and then cleaved (1ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: m/z 343 [M+H]+ for the amide adduct. Step 2c Second reductive alkylation
Figure imgf000018_0001
To a round bottomed flask containing the resin from step 2b (14.5g, 13mmol) was added DMF (100ml) and 3,4-dichlorobenzaldehyde (22.75g, 130mmol, 10eq). After shaking for 10 mins acetic acid (7.8g, 130mmol) was added and the flask agitated for a further 20 mins. Sodium triacetoxyborohydride (27.5g, 130mmol, 10eq) was then added and the reaction mixture agitated for 20 hrs. The resin was collected by filtration and washed with [DMF (3 x 100ml), MeOH (3 x 100ml)] x 3; [DCM (3 x 100ml), MeOH (3 x 100ml)] x 3; 100ml CH2CI2 and TBME (3 x 100ml) and dried in the vacuum oven overnight. To check that the reaction was complete 0.01 g of resin was cleaved (1 ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: m/z 397 [M+H]+.
Step 3 Cleavage of primary amine from resin
Figure imgf000018_0002
To a round bottomed flask containing the resin from step 2c in CH2CI2 (100ml) was added a solution of 1 :1 TFA/CH2CI2 (100ml). After shaking for 1 hr the resin (that was now purple in colour) was collected by filtration and washed with CH2CI2 (100ml). The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude oil was re-solvated in EtOAc (100ml) and washed with sat aq NaHCO3 (100ml) and the aqueous phase was re-extracted with EtOAc (2 x 50ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the desired mixture of diastereomeric products as a yellow oil (6.09g) which was pure enough to use in the next step without further purification. HPLC-MS: m/z 397 [M+Hf.1H NMR (MeOD): 7.39 (s, 0.5H, diastereomer A), 7.38 (s, 0.5H, diastereomer B), 7.33 (d, J = 8 Hz, 0.5H, diastereomer A), 7.32 (d, J= 8 Hz, 0.5H, diastereomer B), 7.11-7.15 (m, 1 H), 4.47-4.78 (br s, 2H), 3.35 (s, 1 H), 3.34 (s, 1 H), 2.67 (d, J = 7 Hz, 1 H), 2.64 (d, J = 7 Hz, 1 H), 2.14 (d, J = 7 Hz, 1 H), 2.02-2.07 (m, 3H), 0.65-1.86 (m, 22H).
B. Typical Guanidine Synthesis
Figure imgf000019_0001
To a solution of the primary amine (1.5g, 3.54mmol) (obtained from step 3 of the primary amine synthesis above) in DMF (1.77ml) was added diisopropylethylamine (548mg, 4.23mmol, 1.2eq) and 1-/-/-pyrazole-1- carboxamidine hydrochloride (570mg, 3.89 mmol, 1.1 eq). The resulting solution was stirred for 20 hrs by which time HPLC-MS showed the reaction to be complete. The solvent was removed in vacuo and the residue purified by column chromatography on SiO2 using 10% MeOH/CH2CI2 as eluent to give the desired mixture of diastereomeric products (Compound 6) as a white powder (450mg, 28% yield). 1H NMR (MeOD): 7.52 (s, 1 H), 7.45 (d, J = 8 Hz, 1 H), 7.25 (d, J = 8 Hz, 1 H), 3.45-3.54 (m, 2H), 3.30-3.34 (m, 1 H), 3.00-3.06 (m, 2H), 2.14-2.31 (m, 4H), 0.76-1.97 (m, 23H). C. Typical Amidine synthesis
Step 1 Preparation of tranexamic acid methyl ester
Figure imgf000020_0001
To a solution of tranexamic acid (10g, 63.7mmol) in MeOH (100ml) under an inert atmosphere at 0°C was added thionyl chloride (11.4g, 95.5mmol, 1.5eq) dropwise. After stirring the reaction at room temperature for 4 hrs HPLC-MS showed the reaction was complete. The solvent was removed in vacuo to leave the desired product as a white crystalline solid (13.25g, 100% yield). HPLC-MS: m/z 172 [M+H]+. 1 H NMR (MeOD): 3.67 (s, 3H), 2.82 (d, J = 7Hz, 2H), 2.34 (tt, J = 13, 4 Hz, 1 H), 2.02-2.08 (m, 2H), 1.88-1.95 (m, 2H), 1.61 -1.72 (m, 1 H), 1.47 (dq, J = 14, 4 Hz, 2H), 1.11 (dq, J = 13, 3 Hz, 2H). 13C NMR (MeOD): 177.7, 52.2, 46.2, 43.9, 36.7, 30.2, 29.3.
Step 2 Double /V-alkylation
Figure imgf000021_0001
To a solution of tranexamic acid methyl ester hydrochloride (5g, 24mmol), sodium iodide (360mg, 2.4mmol, 0.1 eq) and cesium carbonate (27.4g, 84mmol, 3.5eq) in DMF (100ml) at 0°C was added 4-chlorobenzyl bromide (10.36g, 50.4mmol, 2.1 eq). The reaction mixture was stirred at room temperature for 72 hrs after which time HPLC-MS indicated that the reaction was complete. The reaction was quenched by the addition of H2O (20ml) and diluted with EtOAc (200ml). The phases were separated and the organic layer washed with H2O (6 x 20ml). The combined aqueous phase was extracted with EtOAc (2 x 100ml). The organic extracts were then combined, washed with H2O (6 x 20ml), dried over MgSO4, filtered and the solvent removed in vacuo. The crude material was purified by column chromatography on SiO2 using 10% EtOAc/hexane as eluent to give the desired product as a white waxy solid (8.2g, 82% yield). HPLC-MS: m/z 420 [M+H]+. 1H NMR (CDCI3): 7.23-7.29 (m, 8H), 3.65 (s, 3H), 3.44 (s, 4H), 2.13-2.22 (m, 3H), 1.94 (dt, J = 17, 3 Hz, 4H), 1.48-1.60 (m, 1 H), 1.39 (dq, J = 13, 4 Hz, 2H), 0.73 (dq, J = 12, 3 Hz, 2H).13C NMR (CDCI3): 176.5, 138.2, 132.5, 130.0, 128.4, 60.4, 58.1 , 51.5, 43.4, 35.0, 30.5, 28.7.
Step 3 Nitrile formation
Figure imgf000022_0001
To a suspension of anhydrous ammonium chloride (766mg, 14.32mmol, 1.5eq) in dry toluene (50ml), under nitrogen at 0°C, was added trimethyl aluminium (7.2ml, 14.32mmol, 1.5eq, 2M solution in toluene), followed by a solution of the ester from step 2 (4g, 9.55mmol) in toluene (10ml). The resulting mixture was heated at 85°C for 20 hrs. After cooling to room temperature dry MeOH (20ml) was added and stirring continued for 1 hr. The solids were removed by filtration and the filtrate concentrated in vacuo. To the residue was then added thionyl chloride (5ml) and the mixture heated at reflux for 1 hr. The mixture was concentrated in vacuo, re-dissolved in EtOAc (50ml) and washed with sat aq NaHCO3 (2 x 50ml). The organic phase was dried over MgSO4, filtered and the solvent removed in vacuo to give the crude product as a yellow oil (2.31 g, 63% yield) that was used in the next step without further purification. HPLC-MS: m/z 387 [M+H]+.
Step 4 Amidine formation
Figure imgf000022_0002
To a suspension of anhydrous ammonium chloride (956mg, 17.9mmol, 3eq) in dry toluene (30ml) under nitrogen at 0°C was added trimethyl aluminium (8.94ml, 17.9mmol, 3eq, 2M solution in toluene). The mixture was stirred at 0°C for 30 mins by which time efforvescence had ceased. The nitrile (2.3g, 5.96mmol) from step 3 was added as a solution in toluene (10ml) and the reaction heated at 85°C for 36 hrs. The reaction mixture was cooled to room temperature, whereupon MeOH (50ml) was added and the mixture stirred for 1 hr. The precipitated solids were removed by filtration and the solid washed with MeOH (20ml). The filtrate was concentrated in vacuo and the residue purified by column chromatography on SiO2 using 10% MeOH/CH2CI2 to yield the desired amidine (Compound 4) as a white crystalline solid (1.6g, 67% yield). HPLC-MS: m/z 404 [M+H]+. 1H NMR (MeOD): 7.29-7.37 (m, 8H), 3.49 (s, 4H), 2.36 (tt, J = 13, 4 Hz, 1 H), 2.22 (d, J = 7 Hz, 2H), 2.04 (dd, J = 14, 3 Hz, 2H), 1.93 (d, J = 12 Hz, 2H), 1.61-1.72 (m, 1 H), 1.55 (dq, J = 13, 3 Hz, 2H), 0.81 (dq, J= 13, 3 Hz, 2H). 13C NMR (MeOD): 176.5, 139.9, 133.7, 131.5, 129.3, 61.4, 59.3, 43.8, 36.0, 31.7, 30.5.
Preparation of N-[(4-{[di(4-chlorobenzyl)amino]methyl}-cyclohexyl)-methyl]- W-methyl- T'cyanoguanidine (Compound 12)
Step l W-[(4-{[di(4-chlorobenzyl)amino]methyl}-cyclohexyl)-methyl]-amino cyanoiminophenoxide
Figure imgf000023_0001
To a solution of Λ/-{[4-(aminomethyl)cyclohexyl]methyl}-/V-(4-chlorobenzyl)-(4- chlorophenyl)methanamine (100mg, 0.256 mmol, 1 eq) in /-propanol (1ml) was added diphenyl cyanocarbonimidate (64mg, 0.269mmol, 1.05eq). The mixture was stirred at room temperature for 18hrs, the solvent removed in vacuo and the residue purified by column chromatography on SiO2 using 10-25% EtOAc/hexane as eluent to give the desired product as a colourless oil (102mg, 75% yield). HPLC-MS: m/z 535 [M+H]+. 1H NMR (CDCI3): 6.97-7.40 (m, 13H), 6.38-6.50 (m, 1 H), 3.39 (s, 4H), 3.13-3.22 (m, 2H), 2.09-2.19 (m, 2H), 0.61-1.88 (m, 10H).
Step 2
Figure imgf000024_0001
To a solution of Λ/-[(4-{[di(4chlorobenzyl)amino]methyl}-cyclohexyl)-methyl]- amino cyanoiminophenoxide (90mg, 0.168mmol, 1eq) in 1 :1 THF//-propanol (1ml) was added triethylamine (0.35ml, 2.52mmol) and methylamine hydrochloride (113mg, 1.68mmol, 10eq). After stirring for 16hrs the reaction was quenched by the addition of brine (10ml) and extracted with CH2CI2 (2 x 10ml). The combined organic extracts were dried over MgSO , filtered and the solvent removed in vacuo. The residue was purified by column chromatography on SiO2 using 20-50% EtOAc/hexane as eluent to give the desired Λ/-[(4-{[di(4- chlorobenzyl)amino]methyl}-cyclohexyl)-methyl]-Λ/-methyl-/V"cyanoguanidine as a mixture of diastereomeric products, as a colourless oil (11 mg, 14% yield). HPLC-MS: m/z 475 [M+H]+. 1H NMR (MeOD): 7.18-7.22 (m, 8H), 3.36 (s, 4H), 2.90 (d, J= 7 Hz, 1 H, diastereomer A), 2.86 (dt, J= 7 Hz, 1 H, diastereomer B), 2.67 (s, 3H), 2.20 (d, J = 7 Hz, 1 H, diastereomer B), 2.08 (d, J = 7 Hz, 1 H, diastereomer A), 0.55-1.84 (m, 10H).
The following compounds were prepared by methods analogue to those described above:
N-{[4-(aminomethyl)cyclohexyl]methyl}-W-(4-chlorobenzyl)-(4- chlorophenyl)-methanamine (compound 1)
Figure imgf000025_0001
Mixture of diastereomers (1 :1). Mono TFA salt. HPLC-MS: m/z 391 [M+H]+. 1H NMR (MeOD): 7.25-7.35 (m, 8H), 3.44 (s, 4H), 2.73 (d, J = 7Hz, 1 H, diastereomer A), 2.66 (d, J = 7 Hz, 1 H, diastereomer B), 2.30 (d, J = 7 Hz, 1 H, diastereomer B), 2.20 (d, J = 7 Hz, 1 H, diastereomer A), 1.32-1.99 (m, 7H), 0.92- 1.12 (m, 2H), 0.68-0.79 (m, 1 H, diastereomer A).
/V-{[4-(aminomethyl)cyclohexyl]methyl}- V-mesitylmethyl-(3,4- dibromophenyl)-methanamine (Compound 2)
Figure imgf000025_0002
Mixture of diastereomers (1 :1). Mono TFA salt. HPLC-MS: m/z 523 [M+H]+. 1H NMR (MeOD): 7.44-7.52 (m, 2H), 7.04-7.10 (m, 1 H), 6.77 (s, 2H), 4.98 (brs, 3H), 3.43 (d, J = 11 Hz, 2H), 3.29-3.34 (m, 2H), 2.74 (d, J = 7 Hz, 1 H, diastereomer A), 2.58 (d, J = 7 Hz, 1 H, diastereomer B), 2.27-2.30 (m, 4H), 2.25 (s, 3H), 2.20 (s, 3H), 2.12 (d, J = 7 Hz, 1 H, diastereomer A), 1.30-1.90 (m, 7H), 0.82-1.02 (m, 2H), 0.63 (q, J = 13 Hz, 1 H, diastereomer A). Λ/-[(4-{[di(4-chlorobenzyl)amino]methyl}cyclohexyl)methyl]guanidine (Compound 3)
Diastereomer A:
Figure imgf000026_0001
7.19-7.23 (m, 8H), 3.38 (s, 4H), 2.82 (d, J = 7 Hz, 2H), 2.20 (d, J = 7 Hz, 2H), 1.70-1.80 (m, 1 H), 1.20-1.60 (m, 7H), 0.90-1.00 (m, 2H).
Diastereomer B: HPLC-MS: m/z 433 [M+H]+. 1H NMR (MeOD): 7.18-7.24 (m, 8H), 3.38 (s, 4H), 2.89 (d, J = 7 Hz, 2H), 2.10 (d, J = 7 Hz, 2H), 1.83 (brd, J= 13 Hz, 2H), 1.67 (brd, J = 13 Hz, 2H), 1.18-1.48 (m, 2H), 0.86 (q, J = 12 Hz, 2H), 0.61 (q, J = 12 Hz, 2H).
V-[(4-{[(3,4-dibromobenzyl)(mesitylmethyl)amino]methyl}cyclohexyl)- methyl]guanidine (Compound 5)
Figure imgf000026_0002
Mixture of diastereomers (2:1). HPLC-MS: m/z 565 [M+H]+. 1H NMR (MeOD): 7.52-7.58 (m, 2H), 7.09-7.15 (m, 1H), 6.80 (s, 2H), 3.50-3.52 (m, 2H), 3.38-3.41 (m, 2H), 3.00 (d, J = 7 Hz, 0.66H, diastereomer A), 2.88 (d, J = 7 Hz, 1.34H, diastereomer B), 2.19-2.30 (m, 11 H), 1.30-1.90 (m, 7H), 0.60-1.00 (m, 3H). Λ-{[4-({di[4-(tert-butyl)benzyl]amino}methyl)cyclohexyl]methyl}guanidine (Compound 7)
Figure imgf000027_0001
Mixture of diastereomers (3:1). HPLC-MS: m/z 477 [M+H]+. 1H NMR (CDCI3): 7.68 (t, J = 5 Hz, 0.25H, diastereomer A), 7.60 (t, J = 5 Hz, 0.75H, diastereomer B), 7.33 (d, J = 8 Hz, 4H), 7.27 (d, J = 8 Hz, 4H), 3.50 (brs, 4H), 2.89 (t, J = 6 Hz, 0.5H, diastereomer A), 2.77 (t, J = 6 Hz, 1.5H, diasteromer B), 2.28 (d, J = 6 Hz, 1.5 H, diastereomer B), 2.21 (d, J = 6 Hz, 0.5H, diastereomer A), 1.32-1.98 (m, 7H), 1.31 (s, 18H), 0.75-1.02 (m, 3H).
Λ/-[(4-{[(4-chlorobenzyl)(3,4-dichlorobenzyl)amϊno]methyl} cyclohexyl)methyl]-guanidine (Compound 8)
Figure imgf000027_0002
Mixture of diastereomers (1 :1). HPLC-MS: m/z 469 [M+H]+. 1H NMR (MeOD): 7.42-7.50 (m, 2H), 7.23-7.33 (m, 5H), 3.45-3.49 (m, 4H), 3.00 (d, J = 7 Hz, 1 H, diastereomer A), 2.98 (d, J = 7 Hz, 1 H, diastereomer B), 2.32 (d, J = 7 Hz, 1 H, diastereomer B), 2.23 (d, J = 7 Hz, 1 H, diastereomer A), 1.36-2.00 (m, 7H), 0.70- 1.13 (m, 3H). /V-[(4-{[(4-bromobenzyl)(2-methylbutyl)amino]methyl}cyclohexyl)methyl]- guanidine (Compound 9)
Figure imgf000028_0001
Mixture of 4 diastereomers. HPLC-MS: m/z 423 [M+H]+. 1H NMR (MeOD): 7.20- 7.46 (m, 4H), 3.30-3.50 (m, 2H), 2.99-3.04 (m, 2H), 0.70-2.30 (m, 23H).
Λ/-(3-{[di(4-chlorobenzyl)amino]methyl}benzyl)guanidine (Compound 10)
Figure imgf000028_0002
HPLC-MS: m/z 427 [M+H]+. Η NMR (MeOD): 7.29-7.40 (m, 11 H), 7.18-7.22 (m, 1 H), 4.44 (s, 2H), 3.52 (s, 2H), 3.50 (s, 4H).
Λ/-2-[(4-{[di(4-chlorobenzyl)amino]methyl}cyclohexyl)methyl]-4,5-dihydro- 1H-2-imidazolamine (Compound 11)
Figure imgf000028_0003
Mixture of diastereomers (1 :1). HPLC-MS: m/z 459 [M+H]+. Η NMR (MeOD): 7.19-7.23 (m, 8H), 3.62 (s, 4H), 3.42 (s, 4H), 2.95 (d, J = 7 Hz, 1 H, diastereomer A), 2.89 (d, J = 7 Hz, 1 H, diastereomer B), 2.36 (d, J = 7 Hz, 1 H, diastereomer B), 2.14 (d, J = 7 Hz, 1 H, diastereomer A), 1.27-1.90 (m, 7H), 0.60-1.05 (m, 3H).
4-{[di(4-chlorobenzyl)amino]methyl}-1-benzenecarboximidamide (Compound 13)
HPLC-MS: m/z398
Figure imgf000029_0001
(m, 12H), 4.32-4.55 (m, 6H).
V-[(4-{[(4-chlorobenzyl)(2-thienylmethyl)amino]methyl}cyclohexyl)methyl]- guanidine (Compound 14)
Figure imgf000029_0002
Mixture of diastereomers (1 :1). HPLC-MS: m/z 371 [M+H]+. 1H NMR (CDCI3): 7.10-7.40 (m, 8H), 6.84-6.93 (m, 2H), 3.70 (s, 2H), 3.52 (s, 2H), 2.80-2.96 (m, 2H), 2.30 (d, J = 7 Hz, 1 H, diastereomer A), 2.22 (d, J = 7 Hz, 1 H, diastereomer B), 0.70-1.92 (m, 10H). Λ/-(4-chlorobenzyl)-Λ-({4-[(methylamino)methyl]cyclohexyl}methyl)-(4- chlorophenyQmethanamine (Compound 16)
Figure imgf000030_0001
Mixture of diastereomers (1 :1). HPLC-MS: m/z 405 [M+H]+. Η NMR (CDCI3): 8.40 (brs, 1 H), 7.27-7.40 (m, 8H), 4.20 (brs, 4H), 2.62-2.80 (m, 4H), 2.56 (s, 3H), 0.63-1.90 (m, 10H).
Analytical Method
The analytical methods used to characterise compounds comprised HPLC-MS and 1H and 3C NMR.
HPLC-MS instrument comprises:
Hewlett Packard 1312A binary pump
Hewlett Packard 1314A variable wavelength detector (set at 215nm) Gilson 215 autosampler fitted with a 1ml syringe Polymer Labs PL1000 Evaporative Light Scattering Detector (where fitted)
Micromass ZMD mass spectrometer operating in Electrospray positive ionisation mode.
The LC eluent is split, after flowing through the VWD uv detector, and approximately 200μl/min enters the mass spectrometer, 800μl/min to the ELS (where fitted). The instruments were controlled using Micromass MassLynx 3.5 software under Windows NT4.0
HPLC Conditions Mobile Phase: Aqueous - Water + 0.1 % Trifluoroacetic acid
Organic - Acetonitrile + 0.1% Trifluoroacetic acid Gradient:
Figure imgf000031_0001
Run time: 2.4 mins Flow rate: 1 ml/min Injection vol: 3 μl Column temperature: ambient (20°C) Column: 50 x 2.0mm Hypersil C18 BDS; 5μm UV Detector Variable wavelength detector set at 215nm ELS Detector Nebuliser Temperature 80°C
Evaporation temperature 90°C
Gas Flow 1.5 l/hr
MS Detector m/z 150-800 @ 0.5secs/scan, 0.1 second interscan delay
Cone voltage 25V, Source Temp. 140°C
Drying Gas 350 l/hr
NMR
1 H NMR spectra were recorded on a 400MHz Bruker NMR machine.
The above compounds, and others prepared by the above described methods, were tested for antibacterial and antifungal activity according to the protocols described in the Assay Methods section below. The compounds and results are shown in the following Table.
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Table (Continued)
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
94
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
97
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
102
Figure imgf000103_0001
Table (Continued)
Figure imgf000103_0002
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
107
Figure imgf000108_0001
108
Figure imgf000109_0001
109
Figure imgf000110_0001
110
Figure imgf000111_0001
111
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
115
Figure imgf000116_0001
116
Figure imgf000117_0001
117
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
120
Figure imgf000121_0001
Figure imgf000122_0001
122
Figure imgf000123_0001
Assay Methods
The following bacterial and yeast strains were used: Bacillus subtilis 168CA. Candida albicans ATCC 90028, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Haemophilus influenzae ATCC 49247, Pseudomonas aeruginosa 101021 , Saccharomyces cerevisiae MYA-658, Staphylococcus aureus MS 601055 and Streptococcus pneumoniae ATCC 49619.
MICs were determined by the broth microdilution method (National Committee for
Clinical Laboratory Standards. 2000. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard - 5th ed.). Microtitre plates containing the test compounds (standard concentration range: 0.125-64 μg/ml) were inoculated with a starting inoculum of 5x105 cfu/ml.
Mueller-Hinton broth (Oxoid) was used for all non-fastidious organisms. S. pneumoniae and H. influenzae were grown in brain heart infusion (Sigma) supplemented with 5% horse serum and 2 mg of NAD per litre (/-/. influenzae).
The MIC was defined as the lowest concentration of compound inhibiting visible growth.
For S. cerevisiae and C. albicans, Sabouraud dextrose broth (Sigma) was used. Microtitre plates containing the test compounds were inoculated with 1 :100 dilutions of cultures at an absorbance at 600 nm (A6oo) of 0.09. S. cerevisiae and C. albicans were incubated at 30°C for 44-48 h and at 37°C for 28 h, respectively. The MIC was defined as the lowest concentration of compound inhibiting visible growth. The IC50 was defined as a reduction in Aβoo of >50% compared to A6oo of a culture grown in the absence of compound.
Activities were scored as 'A' if the MIC was single digit eg. 8 microgrammes/ml, 'B' if the MIC was 16 to 64 microgrammes/ml and 'C if the MIC was greater than 64 microgammes/ml. The data set in the above table is data collected from B. subtilis, E. coli and S. cerevisiae tests. IC50 values were used to evaluate effects of compounds on the growth of yeast.

Claims

Claims:
1. The use of a compound of formula (I) or a salt, hydrate or solvate thereof in the preparation of a composition for inhibiting microbial growth:
B L -N"Rl CD
I R
wherein
B represents R2R3N-, R2NH-C(=NR3)-, or R2NH-C(=NR3)-NR4- wherein each of R2, R3 and R4 represents hydrogen or a CrC6 alkyl, phenyl, phenyl(CrC6 alkyl)-, monocyclic heteroaryl, monocyclic heteroaryl (CrC6 alkyl)-, or cyano group, or R2 and R3 form a ring together with the nitrogen atoms to which they are attached, .
L represents a divalent radical of formula (II)
-(Alki)m-(Cyci)p-(Alk2)n-[(Alk3)r-(Cyc2)s-(Alk4)t]w- (II)
wherein Alk1, Alk2, Alk3 and Alk4 each independently represent (i) an optionally substituted divalent C1-C3 alkylene radical which may optionally contain an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or C1-C3 alkyl, (ii) an optionally substituted -CH=CH- radical, or (iii) a -C≡C- radical,
Cyc1 and Cyc2 each independently represent an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms,
m, n, p, r, s, t and w each independently represent 0 or 1 , provided that at least one of m, n and p is 1 , R represents an optionally substituted C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Cyc-, (Cyc)-(C C6 alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2- C6 alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms, and
Ri represents an optionally substituted (aryl)-(CrC6 alkyl)-, (aryl)-(C2-C-6 alkenyl)-(aryl)-(C2-C6 alkynyl)-, (heteroaryl)-(CrC6 alkyl)-, (heteroaryl)-(C2- C6 alkenyl)- or (heteroaryl)-(C2-C6 alkynyl)- radical.
2. The use as claimed in claim 1 wherein w is 0.
3. The use as claimed in claim 1 wherein in the compounds (I):
B represents NH2-, CH3NH-, NH2-C(=NH)-, NH2-C(=NH)-NH-
N≡C-NH2-C(=NH)-NH- or ;
Figure imgf000126_0001
L represents a divalent radical of formula (III)
-(Alki)m-(Cyci)p-(Alk2)n- (III)
wherein Alk1, and Alk2 each independently represent an optionally substituted divalent C1-C3 alkylene radical,
Cyc1 represents an optionally substituted divalent monocyclic carbocyclic radical having from 5 to 8 ring atoms,
m, n and p each independently represent 0 or 1 , provided that at least one of m, n and p is 1 , - R represents an optionally substituted CrC6 alkyl, cycloalkyl (C Ce alkyl)- or phenyl(C C6 alkyl)- group and
Ri represents an optionally substituted phenyl(CrC6 alkyl)- group.
4. The use as claimed in any of the preceding claims wherein B represents NHjr, NH2-C(=NH)-, or NH2-C(=NH)-NH-.
5. The use as claimed in any of the preceding claims wherein when present Cyc1 and/or Cyc2 each is independently a cycloalkyl ring of from 5 to 7 ring carbon atoms, or a phenyl ring, and when present Alk1, Alk2, Alk3 and Alk4 each independently represents -CH2- or -CH2CH2-.
6. The use as claimed in any of the preceding claims wherein Ri represents an optionally substituted (aryl)-(CrC6 alkyl)-, (aryl)-(C2-Cβ alkenyl)-(aryl)-(C2-C6 alkynyl)-, (heteroaryl)-(CrC6 alkyl)-, (heteroaryl)-(C2-C6 alkenyl)- or (heteroaryl)- (C2-C6 alkynyl)- radical.
7. The use as claimed in claim 6 wherein Ri represents an optionally substituted benzyl, cyclohexylmethyl, 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3- or 4- pyridyl, or naphthylmethyl ring.
8. The use as claimed in claim 6 or claim 7 wherein in Ri optional substituents are selected from chloro, bromo and iodo, nitro, cyano, trifuoromethyl, Cι-C6 alkyl, C C6 alkoxy, C C6 alkylthio, CrC6 alkylsulfonyl, phenylsulfonyl and methylenedioxy.
9. The use as claimed in claim 7 wherein optional substituents in R1 are lipophilic.
10. The use as claimed in any of the preceding claims wherein R represents an optionally substituted CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or (Cyc)-(C C6 alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2-C6 alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms.
11. The use as claimed in claim 10 wherein Cyc when present is cyclopentyl, cyclohexyl, cyclohexyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-piperidinyl, 2- and 3- thienyl or 2- or 3-furanyl.
12. The use as claimed in any of claims 1 to 9 wherein R is optionally substituted methyl, ethyl, n- or sec-propyl, n-, sec- or t-butyl, straight or branched chain pentyl or hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclopentylmethyl, cycloheptylmethyl, 2-, 3- or 4-pyridylmethyl, 2- or 3-furanylmethyl, 2- or 3-thienylmethyl, N-piperidinylmethyl, or N- morpholinylmethyl.
13. The use as claimed in any of claims 1 to 9 wherein R is methyl, ethyl, n- or sec-propyl, n-, sec- or t-butyl, or phenyl or benzyl, optionally substituted in the phenyl ring by chloro, bromo or iodo, nitro, cyano, trifuoromethyl, methyl, ethyl, t- butyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl or phenylsulfonyl.
14. A method of treatment of microbial infection which comprises administering to the site of infection or to a patient suffering such infection an antimicrobially effective amount of a compound of formula (I) as defined in any of claims 1 to 13, or a salt, hydrate or solvate thereof.
15. A method of treatment of bacterial or fungal infection which comprises administering to the site of infection or to a patient suffering such infection an antibacterially or antifungally effective amount of a compound of formula (I) as defined in any of claims 1 to 13, or a salt, hydrate or solvate thereof.
16. A compound of formula (I) or a salt, hydrate or solvate thereof:
B~ ^N"*1 (I)
I R
wherein
B represents R2R3N-, R2NH-C(=NR3)-, or R2NH-C(=NR3)-NR4- wherein each of R2, R3 and R4 represents hydrogen or a CrCβ alkyl, phenyl, phenyl(CrC6 alkyl)-, monocyclic heteroaryl, monocyclic heteroaryl(C C6 alkyl)-, or cyano group, or R2 and R3 form a ring together with the nitrogen atoms to which they are attached, PROVIDED THAT when B is R2R3N- then R2 and R3 are not both hydrogen.
L represents a divalent radical of formula (II)
-(Alki)m-(Cyci)p-(Alk2)n-[(Alk3)r-(Cyc2)s-(Alk4)t]w- (II)
wherein Alk1, Alk2, Alk3 and Alk4 each independently represent (i) an optionally substituted divalent CrC3 alkylene radical which may optionally contain an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or C1-C3 alkyl, (ii) an optionally substituted -CH=CH- radical, or (iii) a -C≡C- radical,
Cyc1 and Cyc2 each independently represent an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms, m, n, p, r, s, t and w each independently represent 0 or 1 , provided that at least one of m, n and p is 1 ,
R represents an optionally substituted Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Cyc-, (Cyc)-(C C6 alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2-
Cβ alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms, and
Ri represents an optionally substituted (aryl)-(CrC6 alkyl)-, (aryl)-(C2-C6 alkenyl)-(aryl)-(C2-C6 alkynyl)-, (heteroaryl)-(CrC6 alkyl)-, (heteroaryl)-(C2-
Cβ alkenyl)- or (heteroaryl)-(C -C6 alkynyl)- radical.
17 A compound as claimed in claim 16 wherein w is 0
18. A compound as claimed in claim 16 wherein in the compounds (I):
B represents CH3NH-, NH2-C(=NH)-, NH2-C(=NH)-NH-, N≡C-NH2-C(=NH)-NH- or
Figure imgf000130_0001
L represents a divalent radical of formula (III)
-(Alki)m-(Cyci)p-(Alk2)n- (III)
wherein Alk1, and Alk2 each independently represent an optionally substituted divalent CrC3 alkylene radical,
Cyc1 represents an optionally substituted divalent monocyclic carbocyclic radical having from 5 to 8 ring atoms, m, n and p each independently represent 0 or 1 , provided that at least one of m, n and p is 1 ,
R represents an optionally substituted Ci-Ce alkyl, cycloalkyl(CrC6 alkyl)- or phenyl(CrC6 alkyl)- group and
Ri represents an optionally substituted phenyl(C C6 alkyl)- group.
19. A compound as claimed in any of claims 16 to 18 wherein B represents NH2-C(=NH)-, or NH2-C(=NH)-NH-.
20. A compound as claimed in any of the claims 16 to 19 wherein when present Cyc1 and/or Cyc2 each is independently a cycloalkyl ring of from 5 to 7 ring carbon atoms, or a phenyl ring, and when present Alk1, Alk2, Alk3 and Alk4 each independently represents -CH2- or -CH2CH2-.
21. A compound as claimed in any of claims 16 to 20 wherein Ri represents an optionally substituted (aryl)-(CrC6 alkyl)-, (aryl)-(C2-C6 alkenyl)-(aryl)-(C2-C6 alkynyl)-, (heteroaryl)-(C-i-C6 alkyl)-, (heteroaryl)-(C2-Ce alkenyl)- or (heteroaryl)- (C2-C6 alkynyl)- radical.
22. A compound as claimed in claim 21 wherein Ri represents an optionally substituted benzyl, cyclohexylmethyl, 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3- or 4- pyridyl, or naphthylmethyl ring.
23. A compound as claimed in claim 21 or claim 22 wherein in Ri optional substituents are selected from chloro, bromo, iodo, nitro, cyano, trifuoromethyl, CrC6 alkyl, d-Cβ alkoxy, CrC6 alkylthio, C C6 alkylsulfonyl, phenylsulfonyl and methylenedioxy.
24. A compound as claimed in 22 wherein optional substituents in R1 are lipophilic.
25. A compound as claimed in any of claims 16 to 24 wherein R represents an optionally substituted C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or (Cyc)-(CrC6 alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2-C6 alkynyl)- radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms.
26. A compound as claimed in claim 25 wherein Cyc when present is cyclopentyl, cyclohexyl, cyclohexyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or 4- piperidinyl, 2- and 3-thienyl or 2- or 3-furanyl.
27. A compound as claimed in any of claims 16 to 24 wherein R is optionally substituted methyl, ethyl, n- or sec-propyl, n-, sec- or t-butyl, straight or branched chain pentyl or hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclopentylmethyl, cycloheptylmethyl, 2-, 3- or 4-pyridylmethyl, 2- or 3-f uranylmethyl, 2- or 3-thienylmethyl, N-piperidinylmethyl, or N- morpholinylmethyl.
28. A compound as claimed in any of claims 16 to 24 wherein R is methyl, ethyl, n- or sec-propyl, n-, sec- or t-butyl, or phenyl or benzyl, optionally substituted in the phenyl ring by chloro, bromo or iodo, nitro, cyano, trifuoromethyl, methyl, ethyl, t-butyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl or phenylsulfonyl.
29. A pharmaceutical or veterinary composition comprising a compound as defined in any of claims 16 to 28, or a salt hydrate or solvate thereof, together with a pharmaceutically or veterinarily acceptable carrier.
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WO2005097100A3 (en) * 2004-04-06 2005-12-08 Prolysis Ltd Antibacterial agents
WO2005097100A2 (en) * 2004-04-06 2005-10-20 Prolysis Ltd. Antibacterial agents
WO2006015852A1 (en) * 2004-08-10 2006-02-16 Novartis Ag Organic compounds
US9782407B2 (en) 2004-12-31 2017-10-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9040558B2 (en) 2004-12-31 2015-05-26 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis
US9822108B2 (en) 2012-01-13 2017-11-21 Rutgers, The State University Of New Jersey Antimicrobial agents
US9475783B2 (en) 2012-03-21 2016-10-25 Rutgers, The State University Of New Jersey Antimicrobial agents
US9458150B2 (en) 2013-11-08 2016-10-04 Rutgers, The State University Of New Jersey Antimicrobial agents
US10071082B2 (en) 2013-11-08 2018-09-11 Rutgers, The State University Of New Jersey Antimicrobial agents
US11129814B2 (en) 2013-11-08 2021-09-28 Taxis Pharmaceuticals, Inc. Antimicrobial agents
US10513528B2 (en) 2016-02-25 2019-12-24 Taxis Pharmaceuticals, Inc. Synthetic processes and intermediates
WO2018029618A1 (en) 2016-08-11 2018-02-15 Consejo Nacional De Investigaciones Cientificas Y Tecnicas (Conicet) Antibacterial guanidine derivatives
US10857110B2 (en) 2016-08-11 2020-12-08 Consejo Nacional De Investigaciones Cientificas Y Tecnicas (Conicent) Antibacterial compounds
US10774093B2 (en) 2017-03-30 2020-09-15 Taxis Pharmaceuticals, Inc. Synthetic processes and synthetic intermediates

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