WO2004073709A1 - Agents antimicrobiens - Google Patents

Agents antimicrobiens 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
Prior art date
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PCT/GB2004/000621
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English (en)
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/fr

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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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    • A61K31/00—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
    • A61K31/425—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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    • C07C217/54—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
    • 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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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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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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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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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

Des composés de la formule (I) sont des agents antibactériens. Dans ladite formule (I), B représente R2R3N-, R2NH-C(=NR3)-, ou bien R2NH-C(=NR3)-NR4- où R2, R3 et R4 représentent chacun hydrogène ou un groupe C1-C6 alkyle, phényle, phényl (C1-C6 alkyle), un groupe hétéroaryle monocyclique, un groupe hétéroaryl (C1-C6 alkyle) monocyclique, ou bien un groupe cyano, ou encore R2 et R3 forment ensemble avec les atomes d’azote les portant un cycle ; L représente un radical divalent de formule (II) dans laquelle Alk1, Alk2, Alk3 et Alk4 représentent chacun indépendamment (i) un radical alkylène C1-C3 divalent éventuellement substitué pouvant contenir éventuellement une liaison éther (:O-), thioéther (-S-) ou bien amino (:NRA-) dans laquelle RA est hydrogène ou C1-C3 alkyle, (ii) un radical -CH=CH- éventuellement substitué, ou encore (iii) un radical -C≡C- ; Cyc1 et Cyc2 représentent chacun indépendamment un radical monocyclique, carbocyclique ou hétérocyclique divalent éventuellement substitué ayant de 5 à 8 atomes cycliques ; m, n, p, r, s, t et w représentent chacun indépendamment 0 ou 1, à condition qu’au moins un des éléments m, n et p soit égal à 1; R représente C1-C6 alkyle, C2-C6 alcényle, C2-C6 alcynyle, éventuellement substitué, ou bien un radical Cyc, (Cyc)-(C1-C6 alkyle), (Cyc)-(C2-C6 alcényle), ou (Cyc)-(C2-C6 alcynyle), dans lequel Cyc représente un radical monocyclique, carbocyclique ou hétérocyclique ayant de 5 à 8 atomes cycliques ; et R1 représente un radical (aryl)-(C1-C6 alkyle), (aryl)-(C2-C6 alcényl)-(aryl)-(C2-C6 alcynyle), (hétéroaryl)-(C1-C6 alkyle), (hétéroaryl)-(C2-C6 alcényle) ou (hétéroaryl)-(C2-C6 alcynyle) éventuellement substitué.
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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
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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 (fr) 2016-08-11 2018-02-15 Consejo Nacional De Investigaciones Cientificas Y Tecnicas (Conicet) Dérivés de guanidine antibactériens
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US10774093B2 (en) 2017-03-30 2020-09-15 Taxis Pharmaceuticals, Inc. Synthetic processes and synthetic intermediates

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