WO2001055111A1 - Biaryl compounds, their preparation and their use in therapy - Google Patents

Biaryl compounds, their preparation and their use in therapy Download PDF

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Publication number
WO2001055111A1
WO2001055111A1 PCT/GB2001/000362 GB0100362W WO0155111A1 WO 2001055111 A1 WO2001055111 A1 WO 2001055111A1 GB 0100362 W GB0100362 W GB 0100362W WO 0155111 A1 WO0155111 A1 WO 0155111A1
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minutes
retention time
compound according
vacuo
compound
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PCT/GB2001/000362
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French (fr)
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WO2001055111A8 (en
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Martin James Drysdale
Ian David Starkey
Terry Mark Swarbrick
Andrew John Potter
Justin Fairfield Bower
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Ribotargets Limited
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Priority claimed from GB0001926A external-priority patent/GB0001926D0/en
Priority to AU2868601A priority Critical patent/AU2868601A/en
Application filed by Ribotargets Limited filed Critical Ribotargets Limited
Priority to EP01946853A priority patent/EP1250324A1/en
Publication of WO2001055111A1 publication Critical patent/WO2001055111A1/en
Publication of WO2001055111A8 publication Critical patent/WO2001055111A8/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
    • C07D213/24—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
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • 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
    • A61P31/12—Antivirals
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    • 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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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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    • 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
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    • 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
    • C07D333/56—Radicals substituted by oxygen atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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

Definitions

  • the present invention relates to a class of chemical compounds, their preparation and their use in therapy, particularly, in the treatment of viral and bacterial infection.
  • the present inventors have discovered a new class of chemical compounds which are particularly useful in the treatment of viral and bacterial infection.
  • Ar is an aryl group
  • X' is selected from O, S. SO. S0 2 and NR. X 2 is selected from 0. S. SO. S0 2 . NR and CR 2 . X 3 is CR 2 .
  • each R is independently selected from H. C 1 - 12 alkyl and C 3 _ ⁇ 2 aryl. or any two R groups may together comprise a C ⁇ - 6 alkylene chain, and pharmaceutically acceptable derivatives thereof.
  • Ar is an aryl group as herein defined.
  • the aryl group is a monocyclic or fused polycyclic (preferably bicyclic such as [6,5], [6,6] and [5,5] systems) aromatic or heteroaromatic group.
  • Aromatic groups include phenyl and naphthyl.
  • Heteroaromatic groups are generally preferred to the corresponding aromatic group.
  • Heteroaromatic groups may comprise one or more heteroatoms.
  • Monocyclic heteroaromatic groups include pyridyl, pyrrolyl, furanyl, thienyl and thiazolyl.
  • Heteroaromatic groups may be bonded to the rest of the molecule either via a ring carbon atom or via a ring heteroatom.
  • fused bicyclic heteroaromatic groups include [6,5] (such as indolyl, indolinyl, benzofuranyl, benzothienyl), [6,6] (such as quinolinyl, isoquinolinyl, quinoxalinyl) and [5,5] fused bicyclic heteroaromatic groups.
  • Particularly preferred fused bicyclic heteroaromatic groups comprise groups of the structure:
  • Bicyclic heteroaromatic groups of this structure may be bonded to the rest of the molecule via any position, bonding via the 2. 3. 5 or 6 position being preferred.
  • the group Ar may be substituted as herein defined. Where substituted, there are preferably one to three substituents. more prefereably one substituent.
  • X 1 mav be O. S. SO. SO ⁇ or NR.
  • X 1 is O.
  • X may be O. S. SO. SO : . NR or CR : .
  • X " is NR. more preferably NH.
  • X J is CR 2 .
  • X" is CH ; .
  • Y and Y " are independently selected from C
  • Y 1 comprises a direct chain of 1 to 5 carbon atoms linking X 1 and A.
  • Y 1 is an ethylene or ⁇ -phenylene group
  • the direct chain linking X and A has two carbon atoms.
  • Y 1 comprises a C 1 - 5 alkylene group.
  • Y " comprises a direct chain of 1 to 5 carbon atoms linking X " and B.
  • Y " comprises a C 1 - 5 alkylene group.
  • hvdroxylamine -NHOR).
  • hydroxamic acid (-CONROR), hydrazine (-NRNR 2 ).
  • a and B are independently selected from groups comprising a group selected from amine, amidine, guanidine, and aromatic and non-aromatic nitrogen heterocyclic groups.
  • the aromatic and non-aromatic nitrogen heterocyclic groups may be monocyclic (preferably 5 or 6 membered rings) or polycyclic (preferably fused bicyclic. more preferably [6,5], [6.6] and [5.5] systems) and may comprise one or more nitrogen atom.
  • aromatic nitrogen heterocyclic groups examples include pyrrolyl. pyridinyl. 2-.3- and
  • non-aromatic nitrogen heterocyclic groups include pyrrolidinyl. pyrrolidinone. piperidinyl. morpholin> l and piperazinyl groups.
  • the aromatic and non-aromatic nitrogen heterocv project groups may be substituted or unsubstituted.
  • Preferred substituents include amino groups ( -NR;).
  • the aromatic and non- aromatic nitrogen heterocyclic group may be bonded to the rest of the molecule via a ring carbon atom or via a ring nitrogen atom or via a substituent.
  • aromatic and non-aromatic nitrogen heterocyclic groups are cyclic groups which mimic amidine or guanidine groups of the general formulae
  • 2-aminopyridine 2-aminopyrimidine and 2-pyrimidine groups:
  • Each R is independently selected from H, C ⁇ - ⁇ 2 alkyl and C 3 - ⁇ 2 aryl, or any two R groups may together comprise a C ⁇ . 6 alkylene chain.
  • an R group in X " may be combined with an R group in B such that together with Y ⁇ a cyclic link is formed between X 2 and B.
  • alkyl means a branched or unbranched, cyclic or acyclic. saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably a C 1 - 12 . more preferably C
  • the alkyl chain or ring may include ( i.e. be optionally interrupted with and/or terminate with) one or more heteroatoms. such as oxygen, sulphur or nitrogen.
  • alkylene means a branched or unbranched. cyclic or acylic. saturated or unsaturated divalent hydrocarbyl radical.
  • the alkylene group is preferably a C " 1 - 1 - more preferably C 1 - chain.
  • the alkylene group is preferably a C 3 - ⁇ 2 . more preferably C . ⁇ 0 . more preferably comprises a C . C 6 or C 7 ring.
  • the alkylene chain or ring may include (i.e. be interrupted and/or terminate with) one or more heteroatoms such as oxygen, sulfur or nitrogen.
  • aryl means a C 3 . 2 6, preferably C3. 1 2 . aromatic group, such as phenyl or naphthyl. or a heteroaromatic group containing one or more, preferably one. heteroatom.
  • aromatic group such as phenyl or naphthyl. or a heteroaromatic group containing one or more, preferably one. heteroatom.
  • pyridyl pyrrolyl. furanyl. thienyl, thiazolyl. indolyl, indolinyl. benzofuranyl, benzothienyl, quinolinyl. isoquinolinyl, quinoxalinyl. 2-, 3- or 4- pyrimidinyl, benzodiazolyl. benzotriazolyl. imidazolyl, triazolyl and thiazolyl groups.
  • arylene means a divalent hydrocarbyl radical comprising a C3. 12 aromatic group (such as 0-, m- or ;?-phenylene) or heteroaromatic group containing one or more, preferably one, heteroatom (such as a pyridine-2.3-diyl group).
  • aralkylene means a divalent hydrocarbyl radical comprising both alkylene and arylene groups (such as -CH 2 -(o-phenylene)-CH 2 -).
  • alkyl, aryl, alkylene, arylene and aralkv lene groups Ar, Y , Y " and R. and the groups A and B. may be further substituted or unsubstituted.
  • a Ci (methyl) group may be further substituted with a phenyl group to give a benzyl group.
  • Substituents may include carbon containing groups such as alkyl. aryl, aralkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms (e.g. F, Cl.
  • haloalkyl e.g.trifluoromethyl
  • oxygen containing groups such as alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl).
  • ethers e.g alkoxy. alkoxyalkyl. arvloxyalkyl).
  • aldehydes e.g. carboxaldehyde
  • ketones e.g alkylcarbonyl. alkylcarbonylalkyl. arylcarbonyl. arylalkylcarbonyl. arylcarbonylalkyl
  • acids e.g. carboxy, carboxyalkyl
  • acid derivatives such as esters (e.g.
  • mono- or dialkylaminocarbonylamino or arylaminocarbonv lamino nitrogen containing groups such as amines (e.g. amino, mono- or dialkylamino. aminoalkyl, mono- or dialkylaminoalkv l). azides. nitriles (e.g. cyano. cyanoalkyl). nitro: sulfur containing groups such as thiols. thioethers. sulfoxides, and sulfones (e.g. alkylthio, alkylsulfinyl. alkylsulfonyl. alkylthioalkyl, alkylsulfinylalkyl.
  • heteroatom e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazo 1. thiazolyl. isothiazolyl. oxazolyl. oxadiazolyl. thiadiazolyl, pyrrol
  • alkoxy means alkyl-O- and "alkanoyl” means alkyl-CO.
  • Alkyl substituent groups or alkyl-containing substituent groups may comprise one or more further substituents.
  • aryloxy * ' means aryl -O- and '"aryloyl " means aryl -CO.
  • Aryl substituent groups or aryl-containing substituent groups may comprise one or more further substituents.
  • halogen means a fluorine, chlorine, bromine or iodine radical. preferably a fluorine or chlorine radical.
  • a pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, addition compound, or any other compound which upon administration to a recipient is capable of providing (directly or indirectly) a compound of the present invention or a pharmaceutically acceptable metabolite.
  • pharmaceutically acceptable metabolite is meant a metabolite or residue of a compound of the present invention which gives rise to a biological activity exhibited by the present compounds.
  • a "patient” is a mammal (e.g.. such as a human being or other non-human mammal) to whom a compound according to the invention is administered.
  • the term “patient” does not imply that the individual has ever been hospitalized for medical treatment.
  • microorganism refers to a bacterial, viral, prokaryotic or eukaryotic organism which can be viewed microscopically.
  • microorganism as used herein encompasses both bacteria and viruses.
  • anti-microbial properties or “anti-bacterial properties '” or “anti-viral properties” refer to the ability of the compounds according to the invention to inhibit microbial. bacterial, viral growth.
  • inhibiting growth refers to an inhibition in the translation of microbial proteins, which in turn results in an inhibition in microbial replication (and therefore transcription of microbial mRNAs) which in turn results in an inhibition of infection. Any one of these processes (e.g.. translation, replication, transcription, infection) may be assayed to determine the effectiveness of the compounds according to the invention (e.g., defined as the ability of the compound to inhibit growth).
  • inhibiting microbial grow ⁇ Y' refers to an at least two-fold decrease in any of the parameters discussed above (e.g., translation of microbial proteins, replication of microorganisms, transcription of microbial mRNAs, and/or infection by microorganisms). Inhibition can also refer to an at least two fold decrease in an immune response associated with a microbial infection (e.g., such as the accumulation of anti-microbial antibodies or cytokines and/or pyrogens associated with microbial infection). In one embodiment, inhibition is at least 2-fold, at least 10-fold, at least 20- fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold.
  • the compound inhibits translation of a bacterial and/or viral transcript. In still a more preferred embodiment, the compound inhibits translation of a bacterial and/or viral transcript while not inhibiting translation of a mammalian transcript. In one embodiment of the invention, translation is inhibited at least 2-fold. at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold compared to translation of bacterial and/or viral transcripts in a mammalian organism which has not been treated with the compounds according to the invention. In a further embodiment, the compound inhibits bacterial and/or viral replication. According to a further aspect of the present invention there is provided a compound according to the present invention for use in a method of treatment, preferablv in the prophylaxis or treatment of viral infection or bacterial infection.
  • a compound according to the present invention in the manufacture of a medicament for the prophylaxis or treatment of viral infection or bacterial infection.
  • a method of prophylaxis or treatment of viral infection or bacterial infection comprising administration to a patient in need of such treatment an effective dose of a compound according to the present invention.
  • the effective dose of the compound according to the invention is a dose effective to decrease the titer of infectious microorganisms in a patient ' s body.
  • the titer of infectious microorganisms is measured by culturing a bodily sample and counting the number of microorganisms in the sample.
  • the titer of infectious microorganisms is determined by measuring the expression of the bacterial or viral nucleic acids and/or proteins.
  • the effective dose of the compound is a dose effective to restore the immune response of a host (e.g., a patient) to a microorganism to normal (e.g.. to resemble an immune response of an uninfected host).
  • a bodily fluid from a patient is assayed to detect the presence and/or amounts of anti-bacterial or antiviral antibodies.
  • a compound according to the invention is administered to a patient who has both a bacterial and a viral infection.
  • the patient treated has AIDS.
  • the person has AIDS and at least one opportunistic infection.
  • a compound according to the ention is used prophylacticalh .
  • the compound is contacted with a cell or surface thereby to prev ent the growth of microorganisms in proximitv to the cell or surface.
  • the compound is administered to a patient to pre ⁇ ent infection by a microorganism or to reduce the severity of infection (e.g., as measured by determining the titer of the microorganism in a treated vs. an untreated individual).
  • Viral infections include, but are not limited to:
  • Adenovirus acute respiratory disease Arenaviruses Lassa Virus Lassa Fever Astroviridae Astrovirus Enteritis Bunvaviridae Hantavirus Hantavirus Pulmonary Syndrome Phlebo virus Riff Vallev Fever
  • Paramvxoviridae Paramyxoviruses Para-Influenza Rubulaviruses Mumps Morbilliviruses Measles Respiratory Syncytial Virus Papovaviridae Papillomaviruses Warts/Cervical Cancer Polyomaviruses BK and JC Virus
  • Picornaviridae Coxsackie Viruses ( A and B) Viral Myocarditis & Meningitis & Enteritis Hepatitis A Virus Hepatitis
  • the viral infection comprises HIV or HCV infection, more preferably HIV-I or HIV-II.
  • Bacterial infections include, but are not limited to, infections by Gram Positive Bacteria including Bacillus cereus. Bacillus anthracis, Clostridium botulinum, Clostridium difficile. Clostridium tetani, Clostridial perfringens, Corynebacteria diphtheriae. Enterococcus (Streptococcus D), Listeria Monocytogenes, Pneumoccoccal Infections (Streptococcus pneumoniae), Staphylococcal Infections and Streptococcal Infections; Gram Negative Bacteria including Bactcroides. Bordetella pertussis.
  • Vibrio cholera and Yersinia Acid Fast Bacteria including Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Mycobacterium leprae. Atypical Bacteria, Chlamydia. Mycoplasma, Rickettsia, Spirochetes. Treponema pallidum. Borrelia recurrentis. Borrelia burgdorfii and Leptospira icterohemorrhagiae: and other miscellaneous bacteria including Actinomvces and Nocardia.
  • the present invention further provides use of a compound of the present invention to inhibit the binding of Tat to Tar. It is also featuie of the compounds of the present invention that they inhibit translation of bacterial proteins Accordingly the present inv ention further prov ides use of a compound of the piesent in ention to inhibit the translation of bacterial proteins
  • a pharmaceutical composition comprising a compound of the present inv ention in combination with a pharmaceutically acceptable excipient
  • a method of preparing a phamiaceutical composition comprising the step of combining a compound of the present invention with a pharmaceutically acceptable excipient
  • Reagents (i) R'halide. Cs 2 C0 3 ; (ii) ArB(OH) 2 . Pd catalyst; (iii) R 2 R 3 NH. DCE or EtOH. reducing agent: (iv) R ⁇ CH Br PhsP*. base, toluene; (v) H 2 . Pd/C. solvent: (vi) (a) NaBH 4 . solvent, (b) Ph 3 P, CBr 4 ; (vii) HZ 2 R 2 , base, solvent.
  • the biaryl compounds according to the invention have anti-microbial (e.g.. anti-bacterial and/or anti-viral properties).
  • the compounds inhibit microbial growth. Inhibition of microbial growth can be assayed in a number of different wav s. In one embodiment, microbial growth is measured by assaying the translation of microbial proteins, levels of microbial replication, transcription of microbial mRNAs. and infectivitv (e.g., viral titer in cells exposed to a virus).
  • Assays for measuring such parameters include, but are not limited to, immunossays to detect translation products or assays which measure binding of translational regulators to mRNA transcripts (e.g., to measure translation), RT-PCT, or hybridization assays (e.g.. to measure transcription), incorporation of labeled nucleotides or hybridization assays to measure the presence/amount of microbial genomic DNA (e.g.. to measure replication), plate counting assays (e.g., to measure microbial titers), and the like.
  • compounds are synthesized according to the methods described above and the ability of the compounds to inhibition of microbial growth is assayed to identify compounds which produce an at least two-fold decrease in any of the parameters discussed above (e.g.. translation of microbial proteins, replication of microorganisms, transcription of microbial mRNAs. and/or infection by microorganisms).
  • inhibition is at least 2-fold. at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold.
  • activity is measured in vitro, e.g., by measuring the effects of the compounds on bacterial cultures or on cells infected or to be infected with a virus.
  • compounds are selected which inhibit the growth of both bacterial and viral microorganisms.
  • compounds are selected which inhibit the growth of HIV in cells infected or to be infected with the virus.
  • compounds are selected which inhibit the growth of HIV and any of the characteristic microorganisms found in opportunistically infected AIDS patients.
  • compounds according to the inv ention are tested in animal models to determine the effects of the compounds on microbial growth as described abov e.
  • the compounds are tested for their affect on the immune response of an animal to a microbial infection to select compounds which return the immune response to normal (e.g., provide a response similar to that observed in an animal which has not been infected.
  • a bodily fluid e.g., blood
  • the animal may be tested by evaluating any of the parameters discussed above (e.g., translation of microbial proteins, replication of microorganisms, transcription of microbial mRNAs, and/or infection by microorganisms).
  • the compounds according to the invention inhibit translation of a bacterial and/or viral transcript. In still a more preferred embodiment, the compound inhibits translation of a bacterial and/or viral transcript while not inhibiting translation of a mammalian transcript. In one embodiment of the invention, translation is inhibited at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold compared to translation of bacterial and/or viral transcripts in a mammalian organism which has not been treated with the compounds according to the invention. In one embodiment, a reporter gene is cloned downstream an in frame with a bacterial or viral translation initiation sequence, and the activity of the compounds synthesised is assayed by monitoring the presence and/or amount of the protein encoded by the reporter gene.
  • a compound according to the invention which inhibits the binding of the HIV protein Tat to the HIV RNA Tar binding site. Accordingly, the present invention further provides use of a compound of the present invention to inhibit the binding of Tat to Tar. In one embodiment, inhibition is measured directly by measuring binding of Tat to Tar. In another embodiment, inhibition is measured by measuring the production of Tat protein.
  • the compounds according to the invention are tested for their ability to prevent microbial infection.
  • the compounds are contacted to a cell and the ability of a microorganism to grow in proximity to said cell is evaluated.
  • the cell is a cell which is to be infected with a virus, and the cell is contacted with the compound prior to contacting the cell with the virus.
  • the ability of the compounds to be used prophylactically is then evaluated as described above (e.g., by assaying one or more of translation of microbial proteins, replication of microorganisms, transcription of microbial mRNAs. and/orinfection by microorganisms).
  • the compounds according to the invention are contacted with a surface and assayed for their ability to prevent microbial growth on the surface.
  • the medicament employed in the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal. subcutaneous. transdermal. airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
  • oral or parenteral routes including intravenous, intramuscular, intraperitoneal. subcutaneous. transdermal. airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
  • the compounds of the invention will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension.
  • Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate. to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil. liquid paraffin or olive oil.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer ' s solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate. polyvinyl- pyrrolidone and gum tragacanth. and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • the compounds of the invention may also be presented as liposome formulations.
  • a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 10 mg per kilogram body weight per day.
  • the desired dose is preferably presented once daily, but may be dosed as two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form.
  • the compounds are used to prevent or delay the onset of HIV-infection in individuals who are susceptible or at risk of HIV-infection (e.g., intravenous drug users, patients who have had. or are about to receive. a blood transfusion, immunodeficient or immunocompromised patients, gay men. and the like)
  • the method comprises administering to such a patient a prophylactically effective amount (which generally is the same as a therapeutically effective amount) of one or more of the compositions according to the present invention to the patient to delay or prevent an HIV-infection.
  • the compounds are used to treat an already-infected patient (e.g...
  • the compounds may be used by themselves or in conjunction with other drugs (e.g.. protease inhibitors, antibiotics) or other therapies.
  • drugs e.g.. protease inhibitors, antibiotics
  • the compounds of the present invention were synthesized according to the following protocols and characterized by standard spectroscopic techniques including LCMS under the following conditions.
  • Solvents A - Water + 0.1% formic acid + lOmmol ammonium acetate
  • Reagents (i) BrCH2CH 2 NHBoc. Cs 2 C0 3 , DMF; (ii) ArB(OH) 2 , PdCl 2 (PPh 3 )2. DME, Na 2 C0 3 ; (iii) BocNH(CH 2 ) 4 NH 2 , DCE, sodium triacetoxyborohydride; (iv) TFA/DCM, 1/1 ; (v) N,N'-bis-t-butoxycarbonylpyrazolecarboxamidine, N,N-diisopropylethylamine, CH 3 C ⁇ .
  • the bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh.
  • the TFA salt was stirred in acetonitrile, treated with excess N,N-diisopropylethylamine and N,N ' -bis-t-butoxycarbonylpyrazole carboxamidine added. The mixture was stirred overnight at RT then concentrated in vacuo. The residue was partitioned between dichloromethane and water, the organic layer washed with brine and dried over MgS0 .
  • Reagents (i) Br(CH 2 ) 3 NHBoc. Cs 2 C0 3 , DMF; (ii) ArB(OH) 2 , PdCl 2 (PPh 3 ) 2 . DME. Na 2 C0 3 ; (iii) (N,N'-bis-t- butoxycarbonylcarboxamidine)NH(CH 2 ) NH 2 . DCE, sodium triacetoxyborohydride; (iv) TFA/DCM, 1/1.
  • Reagents (i) Br(CH 2 ) 3 ⁇ HBoc, Cs 2 C0 3 , DMF; (ii) ArB(OH) 2 , PdCl 2 (PPh 3 ) 2 , DME. Na 2 C0 3 ; (iii) R'R 2 NH 2 , DCE. sodium triacetoxyborohydride; (iv) TFA DCM. 1/1.
  • Reagents (i) R " NH 2 , DCE, sodium triacetoxyborohydride; (ii) Di-t-butyl dicarbonate.
  • the N-protected phthalimide (1 eq.) was treated with hydrazine hydrate (15 eq.) in EtOH for 18 h then concentrated in vacuo keeping the water bath below 40°C. The residue was dissolved in EtOAc and the organic layer washed exhaustively with water and finally with brine. The organic fraction was dried (MgS0 4 ), concentrated in vacuo and purified by column chromatography on silica, eluting with 75%EtOAc/hexane. then 5%MeOH/DCM.
  • the bis-Boc compound was treated with 1 mL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired mono-guanidine as the bis- trifluoroacetate.
  • Reagents (i) Bis(pinacolato)diboron. KOAc, DMSO. PdCl (dppf) 2 ; (ii) Arylboronic acid. DMF, K 3 P0 4 . PdCl 2 (dppf) 2 ; (iii) (N.N " -bis-t-butoxycarbonyl)NH(CH 2 ) 3 CH 2 NH 2 . DCE. sodium triacetoxyborohydride; (iv) TFA DCM, 1/1.
  • Reagents (i) BnBr. Cs 2 C0 3 . DMF ; (ii) ArB(OH) 2 . DME. K C0 . PdCl 2 (PPh 3 )2 : (iii ) BCl 3 -SMe 2 . DCM; (iv) R,R 2 NH, MeOH-CH 2 Cl 2 (1 : 1 v/v). Amberiyst A-26 borohvdride resin; (v) Boc 2 0. DIPEA, MeCN: (vi) EtOH. Cs 2 C0 3 . then R 3 X, DMF.
  • Reagents (i) N-Boc-bromopropylamine, Cs 2 CU 3 , DMF; (ii) 2-Benzo[b]thiopheneboronic acid, DME, PdCl 2 (PPh 3 ) 2 , K 2 C0 3 ; (iii) (a) ⁇ H 2 OH.HCl, Et 3 N, 1,2-DCE. (b) H 2 , 10%Pd/C, MeOH, CHC1 3 ; (iv) (a) RC0 2 H. HBTU. TEA. (b) TFA/DCM. 1/1.
  • Reagents (i) (a) TFA DCM, (b) 2-Nitro-phenylsulfonyl chloride, TEA. DCM; (ii) RX. Cs 2 C0 3 , DMF; (iii) PhSH. DBU, CH 3 CN: (iv) Boc 2 0. DIPEA, CH 3 CN; (v) l-amino-4- (N.N , -bis-Bocguanidino)butane, NaB(OAc) 3 H, 1,2-DCE; (vi)TFA/DCM, 1/1.
  • DBU (5 eq.) and thiophenol (4 eq.) were stirred together in DMF for 2h hours.
  • the mixture was concentrated in vacuo and partitioned between EtOAc and water, the organic lav er dried (MgS0 ) and concentrated in vacuo.
  • the compound was then re- dissolved in acetonitrile and stirred for 18 hours with di-'butyl dicarbonate (2 eq. ) and di- isopropylethylamine (2 eq. ).
  • the resultant mixture was poured into water and extracted with ethv l acetate.
  • the organic fraction was dried (MgS0 ). filtered and concentrated in vacuo to giv e the desired compound.
  • RNA is titrated in the presence of a constant amount of fluorescent donor (fluorescein- ADP-1 peptide) and compound as described in International Patent Application W099/64625.
  • the assay is performed under competitive conditions, with a two fold excess of competitor RNA (a fully base-paired TAR sequence ) over fluorescein- ADP-1 peptide (the fluorescent donor).
  • the TAR RNA contains a 3 ' dabcyl group.
  • the dabcyl group is a non-fluorescent acceptor for energy transfer from tluorescein (the fluorescent donor).
  • Measurements were made in a 96-well plate reader (Wallac victor) with a fixed wavelength of 490nm and emission at 535 nm.
  • Io vvas determined by an initial measurement of a 95 ⁇ L solution of l OnM Fluoresein-ADP-1 in the presence of 50mM Tris.HCl pH7.5, 80mM KC1 ,1% DMSO 0.01% Triton X-100. 5 ⁇ g/mL BSA . 20nM competitor RNA in the presence l ⁇ M compound. I was then measured following the addition of 5 uL of a 20 X DABCYL-TAR RNA stock solution.
  • Compounds of the present invention showed inhibitory activities in in vitro translation assays utilizing E. coli extracts.
  • the plasmid pBestLuc. which contained the gene for firefly luciferase downstream of an E. coli promoter and a ribosome binding site was used as a template.
  • the activity of the firefly luciferase enzyme resulted in a strong luminescent signal.
  • the luminescence generated was a direct measurement of protein expression and of translation efficiencv.
  • Translation reactions in the presence of compound were started by mixing a translation premix that contained Mg ⁇ . plasmid template, amino acids, nucleotidetriphosphates. phosphocreatine. creatine phosphokinase and folinic acid with the S30 extract that contains RNA polymerase. ribosomes and translation factors (prepared from E.coli MR ⁇ 600 cells) followed bv incubation at 37°C.
  • the activity of the translated luciferase protein was measured by adding an aliquot of the translation reaction to the non-luminescent substrate luciferin and the luminescence measured.
  • the luminescence w as quantified in a luminescence plate reader (Wallac Victor). Compounds were assayed 3-5 times over a range of concentrations and an IC 50 calculated.
  • the in vivo therapeutic efficacy of the compounds of the invention is measured by intramuscular injection to mice experimentally infected with a pathogenic gram positive or gram negative bacterium (e.g. methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile. Klebsiella pneumoniae. Eschericia coli, Haemophilus influenzae. etc.).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus
  • Clostridium difficile Klebsiella pneumoniae. Eschericia coli, Haemophilus influenzae. etc.
  • MRSA strain A27223 can be used.
  • MRSA strain A27223 is prepared for experimental infection by growth on two large Brain Heart Infusion Agar plates. On each plate. 0.5 ml of frozen stock culture is plated out. Plates are then incubated for 18 hours at 30 ° C. The next day each plate is washed with 20 ml of Brain Heart Infusion Broth and then pooled together. A microscopic direct count of microorganisms is done using a 1 : 1000 dilution of plate wash. After a direct count is obtained, the number of organisms per milliliter is calculated. The count is adjusted to the desired amount of inoculum by diluting in 4% hog mucin.
  • the desired challenge (amount of organisms given to mice) is 2.4 x 10 8 cfu/0.5 ml/mouse for MRSA strain A27223.
  • the mice are infected intraperitoneally with 0.5 ml of challenge.
  • Ten non-treated infected mice are used as controls.
  • Mice used are adult male ICR mice.
  • the average weight of the animals should range from 20 to about 26 grams.
  • a PD 50 (protective dose-50. the dose of drug given which protects 50% mice from mortality) runs for 5 da s. During this time, mortality of mice is checked ev ery day and deaths are recorded. The cumulative mortality at each dose level is used to calculate a PD 50 value for each compound. Surviving mice are sacrificed at the end of day 5 by C0 2 inhalation. The actual calculation of PD 50 is performed with a computer program using the Spearman-Karber procedure.
  • a compound according to the invention is effective for the treatment of bacterial infection if it has a PD 5 0 of about 100 mg/kg or less.
  • the in vivo therapeutic efficacy of the compounds of the invention is measured by conventional in vivo antiviral assays including, but not limited to. that described in Letvin. N.L.. Daniel, M.D.. Sehgal. P.K., Desrosiers, R.C., Hunt. R.D.. Waldron. L.M.. MacKey. J.J.. Schmidt. D.K.. Chalifoux. L.V. and King. N.W. Introduction of AIDS-like disease in macaque monkeys with T-cell tropic retrovirus STLV-III. Science, 1985. 230. 71-73. which is incorporated herein by reference.

Abstract

The invention relates to biaryl compounds, their preparation and their use in the treatment of bacterial and viral infection.

Description

BIARYL COMPOUNDS. THEIR PREPARATION AND THEIR USE IN THERAPY
The present invention relates to a class of chemical compounds, their preparation and their use in therapy, particularly, in the treatment of viral and bacterial infection.
Although many pharmaceutical compounds and compositions are available for the treatment of viral and bacterial infections, there remains a continuing need for improved treatments.
The present inventors have discovered a new class of chemical compounds which are particularly useful in the treatment of viral and bacterial infection.
According to the present invention there is provided a compound of the formula
Figure imgf000002_0001
wherein
Ar is an aryl group,
X' is selected from O, S. SO. S02 and NR. X2 is selected from 0. S. SO. S02. NR and CR2. X3 is CR2. Y1 and Y2 are independently selected from Cι-12 alkylene, C4-12 arylene. C -ι6 aralky lene. CO(Ci.i2 alkylene). CO(C4.i2 arylene) and CO(C _i6 aralkylene) groups, A and B are independently selected from groups comprising a group selected from: amine (-NR:), amide (-CONR;). amidine (-C(=NR)NR:). thioamide (-CSNR:). oxime
Figure imgf000002_0002
droxamic acid (-CONROR). hydrazine (-NRXR; ). h> drazone ( =XNR:). sulphonamide
( -SO2NR2). sulphinamide ( -SOXR; ). sulphoximine ( -SO(=XR)- ι. urea (-XRCONR ). guanidine ι -\RC. =\R)NR; .. ana aromatic and non-aromatic mtro en heterocy clic roups. each R is independently selected from H. C 1-12 alkyl and C3_ι2 aryl. or any two R groups may together comprise a Cι-6 alkylene chain, and pharmaceutically acceptable derivatives thereof.
In the compounds of the present invention Ar is an aryl group as herein defined. Preferably, the aryl group is a monocyclic or fused polycyclic (preferably bicyclic such as [6,5], [6,6] and [5,5] systems) aromatic or heteroaromatic group. Aromatic groups include phenyl and naphthyl. Heteroaromatic groups are generally preferred to the corresponding aromatic group. Heteroaromatic groups may comprise one or more heteroatoms. Monocyclic heteroaromatic groups include pyridyl, pyrrolyl, furanyl, thienyl and thiazolyl. Heteroaromatic groups may be bonded to the rest of the molecule either via a ring carbon atom or via a ring heteroatom. Preferred fused bicyclic heteroaromatic groups include [6,5] (such as indolyl, indolinyl, benzofuranyl, benzothienyl), [6,6] (such as quinolinyl, isoquinolinyl, quinoxalinyl) and [5,5] fused bicyclic heteroaromatic groups. [6.5] ring systems, in which a heteroatom may be located at any ring position, are preferred. Particularly preferred fused bicyclic heteroaromatic groups comprise groups of the structure:
Figure imgf000003_0001
wherein X is NH, S or O. Indoles (i.e. where X is NH) are preferred.
Bicyclic heteroaromatic groups of this structure may be bonded to the rest of the molecule via any position, bonding via the 2. 3. 5 or 6 position being preferred.
The group Ar may be substituted as herein defined. Where substituted, there are preferably one to three substituents. more prefereably one substituent.
X1 mav be O. S. SO. SO^ or NR. Preferably. X1 is O.
X may be O. S. SO. SO:. NR or CR:. Preferably. X" is NR. more preferably NH. XJ is CR2. Preferably. X" is CH;.
1 "*
Y and Y" are independently selected from C|.π alkylene. C .ι2 arylene. C .|6 aralkylene. CO(Ci_i2 alkylene). CO(C .ι2 arylene) and CO(C _i6 aralkylene) groups, as herein defined.
Preferably. Y1 comprises a direct chain of 1 to 5 carbon atoms linking X1 and A. For example, if Y1 is an ethylene or ø-phenylene group, the direct chain linking X and A has two carbon atoms. Preferably. Y1 comprises a C 1-5 alkylene group.
Preferably. Y" comprises a direct chain of 1 to 5 carbon atoms linking X" and B. Preferably, Y" comprises a C 1-5 alkylene group.
A and B are independently selected from groups comprising a group selected from amine (-NR2), amide (-CONR2), amidine (-C(=NR)NR2), thioamide (-CSNR2). oxime (=NOR). hvdroxylamine (-NHOR). hydroxamic acid (-CONROR), hydrazine (-NRNR2). hvdrazone (= NR2), sulphonamide (-S02NR2). sulphinamide (-SONR2), sulphoximine (-SO(=NR)-), urea (-NRCONR2), guanidine (-NRC(=NR)NR2), and aromatic and non-aromatic nitrogen heterocyclic groups.
Preferably, A and B are independently selected from groups comprising a group selected from amine, amidine, guanidine, and aromatic and non-aromatic nitrogen heterocyclic groups. Preferably, the amine, amidine and guanidine groups are unsubstituted (i.e. R=H).
The aromatic and non-aromatic nitrogen heterocyclic groups may be monocyclic (preferably 5 or 6 membered rings) or polycyclic (preferably fused bicyclic. more preferably [6,5], [6.6] and [5.5] systems) and may comprise one or more nitrogen atom.
Examples of aromatic nitrogen heterocyclic groups include pyrrolyl. pyridinyl. 2-.3- and
4-pyrimidinyl. quinolinyl. isoquinolinyl. indolinyl. benzodiazolyl. benzotriazolyl. imidazolyl. triazolyl and thiazolyl groups. Examples of non-aromatic nitrogen heterocyclic groups include pyrrolidinyl. pyrrolidinone. piperidinyl. morpholin> l and piperazinyl groups. The aromatic and non-aromatic nitrogen heterocv clic groups may be substituted or unsubstituted. Preferred substituents include amino groups ( -NR;). The aromatic and non- aromatic nitrogen heterocyclic group may be bonded to the rest of the molecule via a ring carbon atom or via a ring nitrogen atom or via a substituent.
Included within the scope of the term aromatic and non-aromatic nitrogen heterocyclic groups are cyclic groups which mimic amidine or guanidine groups of the general formulae
Figure imgf000005_0001
Specific examples include 2-aminopyridine. 2-aminopyrimidine and 2-pyrimidine groups:
Figure imgf000005_0002
Each R is independently selected from H, Cι-ι2 alkyl and C3-ι2 aryl, or any two R groups may together comprise a C ι.6 alkylene chain. For example, an R group in X" may be combined with an R group in B such that together with Y~ a cyclic link is formed between X2 and B.
As used herein, the term "alkyl" means a branched or unbranched, cyclic or acyclic. saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical. Where acyclic, the alkyl group is preferably a C1-12 . more preferably C |. chain. W ere cyclic, the alkyl group is preferably a C3.1 . more preferably C5.10 and more preferably comprises a C5, C6 or C7 ring. The alkyl chain or ring may include ( i.e. be optionally interrupted with and/or terminate with) one or more heteroatoms. such as oxygen, sulphur or nitrogen.
As used herein the term "alkylene" means a branched or unbranched. cyclic or acylic. saturated or unsaturated divalent hydrocarbyl radical. Where
Figure imgf000005_0003
clic the alkylene group is preferably a C" 1-1 - more preferably C 1- chain. Where cy clic, the alkylene group is preferably a C3-ι2. more preferably C .ι0. more preferably comprises a C . C6 or C7 ring. The alkylene chain or ring may include (i.e. be interrupted and/or terminate with) one or more heteroatoms such as oxygen, sulfur or nitrogen.
As used herein, the term "aryl" means a C3.26, preferably C3.12. aromatic group, such as phenyl or naphthyl. or a heteroaromatic group containing one or more, preferably one. heteroatom. such as pyridyl, pyrrolyl. furanyl. thienyl, thiazolyl. indolyl, indolinyl. benzofuranyl, benzothienyl, quinolinyl. isoquinolinyl, quinoxalinyl. 2-, 3- or 4- pyrimidinyl, benzodiazolyl. benzotriazolyl. imidazolyl, triazolyl and thiazolyl groups.
As used herein the term "arylene" means a divalent hydrocarbyl radical comprising a C3.12 aromatic group (such as 0-, m- or ;?-phenylene) or heteroaromatic group containing one or more, preferably one, heteroatom (such as a pyridine-2.3-diyl group).
As used herein the term "aralkylene" means a divalent hydrocarbyl radical comprising both alkylene and arylene groups (such as -CH2-(o-phenylene)-CH2-).
The alkyl, aryl, alkylene, arylene and aralkv lene groups Ar, Y , Y" and R. and the groups A and B. may be further substituted or unsubstituted. For example, a Ci (methyl) group may be further substituted with a phenyl group to give a benzyl group. Substituents may include carbon containing groups such as alkyl. aryl, aralkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms (e.g. F, Cl. Br and I) and halogen containing groups such as haloalkyl (e.g.trifluoromethyl): oxygen containing groups such as alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl). ethers (e.g alkoxy. alkoxyalkyl. arvloxyalkyl). aldehydes (e.g. carboxaldehyde). ketones (e.g alkylcarbonyl. alkylcarbonylalkyl. arylcarbonyl. arylalkylcarbonyl. arylcarbonylalkyl) acids (e.g. carboxy, carboxyalkyl). acid derivatives such as esters (e.g. alkoxycarbonyl alkoxycarbonylalkyl. alkylcarbonylyoxy. alkylcarbonylyoxyalkyl) and amides (e.g aminocarbonyl. mono- or dialkylaminocarbonyl. aminocarbonylalkyl. mono- or dialkylaminocarbonylalkyl. arylaminocarbonyl); and carbamates (eg. alkoxycarbonylamino. aryloxycarbonylamino. aminocarbonyloxy. mono- or dialkylaminocarbonyloxy. arylaminocarbonyloxy). and ureas (eg. mono- or dialkylaminocarbonylamino or arylaminocarbonv lamino): nitrogen containing groups such as amines (e.g. amino, mono- or dialkylamino. aminoalkyl, mono- or dialkylaminoalkv l). azides. nitriles (e.g. cyano. cyanoalkyl). nitro: sulfur containing groups such as thiols. thioethers. sulfoxides, and sulfones (e.g. alkylthio, alkylsulfinyl. alkylsulfonyl. alkylthioalkyl, alkylsulfinylalkyl. alkylsulfonylalkyl. arylthio, arylsulfi 1.
Figure imgf000007_0001
l. arylthioalkyl. arylsulfmylalkyl. arylsulfonylalkyl); and heterocyclic groups containing one or more, preferably one. heteroatom (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazo 1. thiazolyl. isothiazolyl. oxazolyl. oxadiazolyl. thiadiazolyl, pyrrolidinyl,
Figure imgf000007_0002
l. imidazolidinyl, imidazolinyl, pyrazolidinyl. tetrahydrofuranyl, pyranyl, pyronyl, pyridj l. pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl. thianaphthv l. benzofuranyl. isobenzofuranvl, indolvl. oxyindolvl, isoindolyl, indazolvl. indolinyl. 7-azaindoKl. benzopyranyl, coumarinyl. isocoumarinyl, quinolinyl, isoquinolinyl. naphthridinyl. cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl. chromenyl, chromanyl. isochromanyl, phthalazinyl and carbolinyl).
As used herein, the term "alkoxy" means alkyl-O- and "alkanoyl" means alkyl-CO. Alkyl substituent groups or alkyl-containing substituent groups may comprise one or more further substituents. As used herein, the term "aryloxy*' means aryl -O- and '"aryloyl" means aryl -CO. Aryl substituent groups or aryl-containing substituent groups may comprise one or more further substituents.
As used herein, the term "halogen" means a fluorine, chlorine, bromine or iodine radical. preferably a fluorine or chlorine radical.
By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, addition compound, or any other compound which upon administration to a recipient is capable of providing (directly or indirectly) a compound of the present invention or a pharmaceutically acceptable metabolite. By "pharmaceutically acceptable metabolite" is meant a metabolite or residue of a compound of the present invention which gives rise to a biological activity exhibited by the present compounds.
As used herein, a "patient" is a mammal (e.g.. such as a human being or other non-human mammal) to whom a compound according to the invention is administered. The term "patient" does not imply that the individual has ever been hospitalized for medical treatment.
As used herein, a "microorganism" refers to a bacterial, viral, prokaryotic or eukaryotic organism which can be viewed microscopically. The term "microorganism" as used herein encompasses both bacteria and viruses.
As used herein, "anti-microbial properties" or "anti-bacterial properties'" or "anti-viral properties" refer to the ability of the compounds according to the invention to inhibit microbial. bacterial, viral growth. As defined herein, "inhibiting growth" refers to an inhibition in the translation of microbial proteins, which in turn results in an inhibition in microbial replication (and therefore transcription of microbial mRNAs) which in turn results in an inhibition of infection. Any one of these processes (e.g.. translation, replication, transcription, infection) may be assayed to determine the effectiveness of the compounds according to the invention (e.g., defined as the ability of the compound to inhibit growth). As defined herein, "inhibition of microbial growύY' refers to an at least two-fold decrease in any of the parameters discussed above (e.g., translation of microbial proteins, replication of microorganisms, transcription of microbial mRNAs, and/or infection by microorganisms). Inhibition can also refer to an at least two fold decrease in an immune response associated with a microbial infection (e.g., such as the accumulation of anti-microbial antibodies or cytokines and/or pyrogens associated with microbial infection). In one embodiment, inhibition is at least 2-fold, at least 10-fold, at least 20- fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold.
In a preferred embodiment of the invention, the compound inhibits translation of a bacterial and/or viral transcript. In still a more preferred embodiment, the compound inhibits translation of a bacterial and/or viral transcript while not inhibiting translation of a mammalian transcript. In one embodiment of the invention, translation is inhibited at least 2-fold. at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold compared to translation of bacterial and/or viral transcripts in a mammalian organism which has not been treated with the compounds according to the invention. In a further embodiment, the compound inhibits bacterial and/or viral replication. According to a further aspect of the present invention there is provided a compound according to the present invention for use in a method of treatment, preferablv in the prophylaxis or treatment of viral infection or bacterial infection.
According to a further aspect of the present invention there is provided use of a compound according to the present invention in the manufacture of a medicament for the prophylaxis or treatment of viral infection or bacterial infection.
According to a further aspect of the present invention there is provided a method of prophylaxis or treatment of viral infection or bacterial infection comprising administration to a patient in need of such treatment an effective dose of a compound according to the present invention.
In one embodiment, the effective dose of the compound according to the invention is a dose effective to decrease the titer of infectious microorganisms in a patient's body. In one embodiment, the titer of infectious microorganisms is measured by culturing a bodily sample and counting the number of microorganisms in the sample. In another embodiment, the titer of infectious microorganisms is determined by measuring the expression of the bacterial or viral nucleic acids and/or proteins. In a further embodiment, the effective dose of the compound is a dose effective to restore the immune response of a host (e.g., a patient) to a microorganism to normal (e.g.. to resemble an immune response of an uninfected host). For example, in one embodiment, a bodily fluid from a patient is assayed to detect the presence and/or amounts of anti-bacterial or antiviral antibodies.
In one embodiment, a compound according to the invention is administered to a patient who has both a bacterial and a viral infection. In one embodiment, the patient treated has AIDS. In another embodiment, the person has AIDS and at least one opportunistic infection.
In another embodiment, a compound according to the
Figure imgf000009_0001
ention is used prophylacticalh .
In one embodiment, the compound is contacted with a cell or surface thereby to prev ent the growth of microorganisms in proximitv to the cell or surface. In one embodiment, the compound is administered to a patient to pre\ ent infection by a microorganism or to reduce the severity of infection (e.g., as measured by determining the titer of the microorganism in a treated vs. an untreated individual).
Viral infections include, but are not limited to:
Family Virus Disease Adenoviruses Adenovirus acute respiratory disease Arenaviruses Lassa Virus Lassa Fever Astroviridae Astrovirus Enteritis Bunvaviridae Hantavirus Hantavirus Pulmonary Syndrome Phlebo virus Riff Vallev Fever
Calciviridae Hepatitis E Filoviridae Ebola Virus Marburg Virus Flaviviridae Japanese Encephalitis Virus Hepatitis C Virus Dengue Virus Dengue Haemorrhasic Fever Yellow Fever Virus Hepatitis G Virus Hepadnaviridae Hepatitis B Virus Hepatitis D (delta) Virus Herpesviridae Herpes Simplex Virus 1 Herpes Simplex Virus 2 Cytomegalovirus (CMV) Epstein Barr Virus (EBV) Mononucleosis Varicello Zoster Virus (VZV) Chicken Pox/Shinsles HHV-6 HHV-7 KSHV/HHV8 Kaposi Sarcoma Orthomvxoviruses Influenza Vi s
Paramvxoviridae Paramyxoviruses Para-Influenza Rubulaviruses Mumps Morbilliviruses Measles Respiratory Syncytial Virus Papovaviridae Papillomaviruses Warts/Cervical Cancer Polyomaviruses BK and JC Virus
Parvoviridae Parvoviruses Erythema Infectiosum
Picornaviridae Coxsackie Viruses ( A and B) Viral Myocarditis & Meningitis & Enteritis Hepatitis A Virus Hepatitis
Polioviruses Poliomyelitis
Rhinoviruses Cold
Reoviridae Astroviruses Diarrhoea
Caliciviruses Diarrhoea
Reoviruses Diarrhoea
Rhabdoviridae Lyssavirus Rabies
Retroviridae HIV-1 and HIV-2 AIDS
HTLV-1 and HTLV-2 Leukaemia
Preferably, the viral infection comprises HIV or HCV infection, more preferably HIV-I or HIV-II.
Bacterial infections include, but are not limited to, infections by Gram Positive Bacteria including Bacillus cereus. Bacillus anthracis, Clostridium botulinum, Clostridium difficile. Clostridium tetani, Clostridial perfringens, Corynebacteria diphtheriae. Enterococcus (Streptococcus D), Listeria Monocytogenes, Pneumoccoccal Infections (Streptococcus pneumoniae), Staphylococcal Infections and Streptococcal Infections; Gram Negative Bacteria including Bactcroides. Bordetella pertussis. Brucella, Campylobacter Infections, Enterohemmorrhagic Escherichia coli (EHEC/E.coli 0157:H7). Enteroinvasive Escherichia coli (EIEC), Enterotoxigenic Escherichia coli (ETEC). Haemophilus influenzae. Helicobacter pylori, Klebsiella pneumonia. Legionella spp.. Moraxella catarrhalis. Neisseria gonnorrhoeae. Neisseria meningitidis, Proteus spp.. Pseudomonas aeruginosa, Salmonella spp., Shigella spp.. Vibrio cholera and Yersinia; Acid Fast Bacteria including Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Mycobacterium leprae. Atypical Bacteria, Chlamydia. Mycoplasma, Rickettsia, Spirochetes. Treponema pallidum. Borrelia recurrentis. Borrelia burgdorfii and Leptospira icterohemorrhagiae: and other miscellaneous bacteria including Actinomvces and Nocardia.
It is a feature of the compounds of the present invention that they inhibit the binding of the HIV protein Tat to the HIV RNA Tar binding site. Accordingly, the present invention further provides use of a compound of the present invention to inhibit the binding of Tat to Tar. It is also featuie of the compounds of the present invention that they inhibit translation of bacterial proteins Accordingly the present inv ention further prov ides use of a compound of the piesent in ention to inhibit the translation of bacterial proteins
According to a furthei aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present inv ention in combination with a pharmaceutically acceptable excipient
According to a further aspect of the present invention there is provided a method of preparing a phamiaceutical composition comprising the step of combining a compound of the present invention with a pharmaceutically acceptable excipient
According to a further aspect of the present invention there is provided a piocess for the preparation of the compounds of the present invention The compounds of the present invention may be prepared accoiding to the following general reaction scheme
General Reaction Scheme
Figure imgf000012_0001
Reagents (i) R'halide. Cs2C03; (ii) ArB(OH)2. Pd catalyst; (iii) R2R3NH. DCE or EtOH. reducing agent: (iv) R~CH Br PhsP*. base, toluene; (v) H2. Pd/C. solvent: (vi) (a) NaBH4. solvent, (b) Ph3P, CBr4; (vii) HZ2R2, base, solvent.
The biaryl compounds according to the invention have anti-microbial (e.g.. anti-bacterial and/or anti-viral properties). In one embodiment, the compounds inhibit microbial growth. Inhibition of microbial growth can be assayed in a number of different wav s. In one embodiment, microbial growth is measured by assaying the translation of microbial proteins, levels of microbial replication, transcription of microbial mRNAs. and infectivitv (e.g., viral titer in cells exposed to a virus). Assays for measuring such parameters are well known in the art and include, but are not limited to, immunossays to detect translation products or assays which measure binding of translational regulators to mRNA transcripts (e.g., to measure translation), RT-PCT, or hybridization assays (e.g.. to measure transcription), incorporation of labeled nucleotides or hybridization assays to measure the presence/amount of microbial genomic DNA (e.g.. to measure replication), plate counting assays (e.g., to measure microbial titers), and the like.
In one embodiment, compounds are synthesized according to the methods described above and the ability of the compounds to inhibition of microbial growth is assayed to identify compounds which produce an at least two-fold decrease in any of the parameters discussed above (e.g.. translation of microbial proteins, replication of microorganisms, transcription of microbial mRNAs. and/or infection by microorganisms). In one embodiment, inhibition is at least 2-fold. at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold. In one embodiment, activity is measured in vitro, e.g., by measuring the effects of the compounds on bacterial cultures or on cells infected or to be infected with a virus. In another embodiment, compounds are selected which inhibit the growth of both bacterial and viral microorganisms. In one embodiment, compounds are selected which inhibit the growth of HIV in cells infected or to be infected with the virus. In still another embodiment, compounds are selected which inhibit the growth of HIV and any of the characteristic microorganisms found in opportunistically infected AIDS patients.
In another embodiment, compounds according to the inv ention are tested in animal models to determine the effects of the compounds on microbial growth as described abov e. In one embodiment, the compounds are tested for their affect on the immune response of an animal to a microbial infection to select compounds which return the immune response to normal (e.g., provide a response similar to that observed in an animal which has not been infected. For example, in one embodiment, a bodily fluid (e.g., blood) is obtained from an infected animal at various time points after administering a compound according to the invention to determine the presence or absence of antibodies specific for microbial antigens and/or the presence or absence of cytokines characteristic of microbial infection. Additionally, or alternatively, the animal may be tested by evaluating any of the parameters discussed above (e.g., translation of microbial proteins, replication of microorganisms, transcription of microbial mRNAs, and/or infection by microorganisms).
In a preferred embodiment, the compounds according to the invention inhibit translation of a bacterial and/or viral transcript. In still a more preferred embodiment, the compound inhibits translation of a bacterial and/or viral transcript while not inhibiting translation of a mammalian transcript. In one embodiment of the invention, translation is inhibited at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, or at least 100-fold compared to translation of bacterial and/or viral transcripts in a mammalian organism which has not been treated with the compounds according to the invention. In one embodiment, a reporter gene is cloned downstream an in frame with a bacterial or viral translation initiation sequence, and the activity of the compounds synthesised is assayed by monitoring the presence and/or amount of the protein encoded by the reporter gene.
In a preferred embodiment, a compound according to the invention is provided which inhibits the binding of the HIV protein Tat to the HIV RNA Tar binding site. Accordingly, the present invention further provides use of a compound of the present invention to inhibit the binding of Tat to Tar. In one embodiment, inhibition is measured directly by measuring binding of Tat to Tar. In another embodiment, inhibition is measured by measuring the production of Tat protein.
In another embodiment, the compounds according to the invention are tested for their ability to prevent microbial infection. For example, in one embodiment, the compounds are contacted to a cell and the ability of a microorganism to grow in proximity to said cell is evaluated. In one embodiment, the cell is a cell which is to be infected with a virus, and the cell is contacted with the compound prior to contacting the cell with the virus. The ability of the compounds to be used prophylactically is then evaluated as described above (e.g., by assaying one or more of translation of microbial proteins, replication of microorganisms, transcription of microbial mRNAs. and/orinfection by microorganisms). In a further embodiment, the compounds according to the invention are contacted with a surface and assayed for their ability to prevent microbial growth on the surface.
The medicament employed in the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal. subcutaneous. transdermal. airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension.
Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate. to delay absorption in the gastrointestinal tract.
Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil. liquid paraffin or olive oil.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
For intramuscular, intraperitoneal. subcutaneous and intravenous use. the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate. polyvinyl- pyrrolidone and gum tragacanth. and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
The compounds of the invention may also be presented as liposome formulations.
In general a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 10 mg per kilogram body weight per day. The desired dose is preferably presented once daily, but may be dosed as two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form.
In a preferred method according to the present invention, the compounds are used to prevent or delay the onset of HIV-infection in individuals who are susceptible or at risk of HIV-infection (e.g., intravenous drug users, patients who have had. or are about to receive. a blood transfusion, immunodeficient or immunocompromised patients, gay men. and the like) The method comprises administering to such a patient a prophylactically effective amount (which generally is the same as a therapeutically effective amount) of one or more of the compositions according to the present invention to the patient to delay or prevent an HIV-infection. In another embodiment of the invention, the compounds are used to treat an already-infected patient (e.g.. an HIV-positive patient) to prev ent re-infection and to inhibit viral replication and 'or further infection by opportunistic microorganisms. The compounds may be used by themselves or in conjunction with other drugs (e.g.. protease inhibitors, antibiotics) or other therapies.
The invention will now be described with reference to the following Examples. It will be appreciated that what follows is by way of example only and that modifications to detail may be made whilst still falling within the scope of the invention.
EXPERIMENTAL
Chemical Synthesis
The compounds of the present invention were synthesized according to the following protocols and characterized by standard spectroscopic techniques including LCMS under the following conditions.
HPLC: HP 1100
Column: ABZ+, 3.3cm*4.6mmD
Temperature: 20°C
Solvents: A - Water + 0.1% formic acid + lOmmol ammonium acetate
B - 95% Acetonitrile/water + 0.05% formic acid Flow rate: 1 mL/min Gradient: Total time 8 minutes
- 100% A for 0.7 minutes
- ramp up to 100% B over 3.5 minutes
- 100% B for 3.5 minutes - ramp down to 0% B over 0.3 minutes
Detection: UV detection at 230nm. 254nm and 270nm
Mass spec: HP1100 MSD Method: Electrospray, +"ve ion
Figure imgf000018_0001
Reagents: (i) BrCH2CH2NHBoc. Cs2C03, DMF; (ii) ArB(OH)2, PdCl2(PPh3)2. DME, Na2C03; (iii) BocNH(CH2)4NH2, DCE, sodium triacetoxyborohydride; (iv) TFA/DCM, 1/1 ; (v) N,N'-bis-t-butoxycarbonylpyrazolecarboxamidine, N,N-diisopropylethylamine, CH3CΝ.
Scheme 1
The following examples were synthesized using the procedures outlined in Scheme 1.
Example 1
Figure imgf000018_0002
To 5-bromosalicylaldehyde (leq.) and cesium carbonate (2 eq.) in DMF at RT was added l-bromo-2-iV-t-butoxycarbonylethane (1.2 eq.). and the mixture stirred overnight at RT.
The DMF was evaporated in vacuo and the residue partitioned between EtOAc and water.
The organic layer was washed with brine and dried over MgS0 . Concentration gave 1 as a solid, which was crystallized from hexane. LC retention time 4.56 minutes. [M+Hf 345. Example 2
Figure imgf000019_0001
Figure imgf000019_0002
To a mixture of the aldehyde of example 1 (1 eq.), dichlorobis(triphenylphosphine)- palladium(II) (10mol%) and 2N Na2C03 (eq.) was added phenylboronic acid (1.5eq.) in dry, degassed DME and the mixture heated at 80°C for 16h. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgSO . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane.
LC retention time 4.75 minutes. [M+Na]+ 364.
b)
Figure imgf000019_0003
The aldehyde (1 eq.) and mono-.V-t-butoxycarbonyl-1.4-diaminobutane (2 eq.) were stirred at RT for 15min in 1.2-dichloroethane. and then sodium triacetoxyborohydride (1.5 eq.) was added. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 3.79 minutes. [M+H]+ 514.
c)
Figure imgf000020_0001
The bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh.
The volatiles were removed in vacuo and the TFA salt used without further purification.
The TFA salt was stirred in acetonitrile, treated with excess N,N-diisopropylethylamine and N,N'-bis-t-butoxycarbonylpyrazole carboxamidine added. The mixture was stirred overnight at RT then concentrated in vacuo. The residue was partitioned between dichloromethane and water, the organic layer washed with brine and dried over MgS0 .
Concentration gave an oil, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 4.44 minutes, [M+H]+ 799.
d) The fully protected bis-guanidine was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired bis-guanidine as the tris-trifluoro ac etate . LC retention time 0.53 and 2.64 minutes, [M+H]+ 398.
Example 3
Figure imgf000020_0002
As example 2 using -tolylboronic acid.
LC retention time 2.78 minutes. [M+H]τ 412. Example 4
Figure imgf000021_0001
As example 2 using 4-methoxyphenylboronic acid. LC retention time 2.71 minutes, [M+H]+ 428.
Example 5
Figure imgf000021_0002
As example 2 using 4-fluorophenylboronic acid. LC retention time 2.71 minutes, [M+H]+ 416.
Example 6
Figure imgf000021_0003
As example 2 using 2-thienylboronic acid. LC retention time 0.50 and 2.62 minutes. [M+Hf 404.
Example 7
Figure imgf000022_0001
As example 2 using 3-thienylboronic acid.
LC retention time 0.51 and 2.58 minutes, [M+H]+ 404.
Example 8
Figure imgf000022_0002
As example 2 using benzo[b]thiophene-2-boronic acid. LC retention time 2.92 minutes, [M+H]+ 454.
Example 9
Figure imgf000022_0003
As example 2 using benzo[b]ftιran-2-boronic acid. LC retention time 2.85 minutes, [M+H]+ 438. 17
Figure imgf000023_0001
Reagents: (i) Br(CH2)3NHBoc. Cs2C03, DMF; (ii) ArB(OH)2, PdCl2(PPh3)2. DME. Na2C03; (iii) (N,N'-bis-t- butoxycarbonylcarboxamidine)NH(CH2) NH2. DCE, sodium triacetoxyborohydride; (iv) TFA/DCM, 1/1.
Scheme 2
The following examples were synthesized using the procedures outlined in Scheme 2.
Example 10
Figure imgf000023_0002
To 5-bromosalicylaldehyde (1 eq) and cesium carbonate (2 eq) in DMF at RT was added l-bromo-3-N-t-butoxycarbonylpropane (1.2) and the mixture stirred overnight at RT. The
DMF was evaporated in vacuo and the residue partitioned between EtOAc and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave the desired aldehyde as a solid, which was crystallized from hexane.
LC retention time 4.68 minutes. [M+H]" 380. /J
Example 1 1
Figure imgf000024_0001
a)
Figure imgf000024_0002
To a mixture of the aldehyde (1 eq) of example 10. dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2C03 was added p-tolylboronic acid (2 eq) in dry, degassed DME and the mixture heated at 80°C for 16h. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane.
LC retention time 4.79 minutes, [M+H-Boc]+ 286.
b)
Figure imgf000024_0003
The aldehyde (1 eq) and l-amino-4-X.V-bis-t-butoxycarbonylguanidinobutane (1.8 eq) were stirred at RT for 15min in 1.2-dichloroethane. then sodium triacetoxyborohydride (1.5 eq) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS04. Concentration gave a solid, which was purified bv chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 4.18 minutes. [M+H]" 700.
c) The tris-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired mono-guanidine as the tris- trifluoroacetate.
LC retention time 2.69 minutes, [M+H]+ 400.
Example 12
Figure imgf000025_0001
As example 11 using 4-fluorophenylboronic acid. LC retention time 2.68 minutes. [M+H]+ 388.
Figure imgf000025_0002
As example 11 using 3-thienylboronic acid. LC retention time 0.49 and 2.56 minutes. [M+H]~ 376.
Example 14
.(X „ \ „\H
H
I I \ " M l As example 1 1 using benzo[b]thiophene-2-boronic acid. LC retention time 2.91 minutes, [M^H]+ 426.
Example 15
Figure imgf000026_0001
As example 1 1 using benzo[b]furan-2-boronic acid. LC retention time 2.84 minutes, [M+Hf 410.
Example 16
Figure imgf000026_0002
As example 11 using 4-trifluoromethylbenzeneboronic acid. LC retention time 2.90 minutes, [M+H]+ 438.
Example 17
Figure imgf000026_0003
As example 11 using naphthyl-1-boronic acid. LC retention time 2.87 minutes. [M-rH]" 420. Example 18
Figure imgf000027_0001
As example 11 using naphthyl-2-boronic acid. LC retention time 2.87 minutes, [M+H]+ 420.
Example 19
Figure imgf000027_0002
As example 11 using l-N-Boc-indole-2-boronic acid. LC retention time 2.76 minutes, [M+H]+ 410.
Figure imgf000027_0003
Reagents: (i) Br(CH2)3ΝHBoc, Cs2C03, DMF; (ii) ArB(OH)2, PdCl2(PPh3)2, DME. Na2C03; (iii) R'R2NH2, DCE. sodium triacetoxyborohydride; (iv) TFA DCM. 1/1.
Scheme 3
The following examples were synthesized using the procedures outlined in Scheme 3. Example 20
Figure imgf000028_0001
To a mixture of the aldehyde (1 eq) of example 10, dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2Cθ3 was added benzo[έ>]furan-2-boronic acid acid (2 eq) in dry, degassed DME and the mixture heated at 80°C for 16h. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane. LC retention time 5.17 minutes, [M+Na]+ 418.
Example 21
Figure imgf000028_0002
a)
Figure imgf000028_0003
The aldehyde (1 eq.) from example 20 and mono-N.N'-bis-t-butoxycarbonylguanidino-m- xylenediamine (2 eq.) were stirred at RT for 15min in 1.2-dichloroethane. then sodium triacetoxyborohydride (1.5 eq.) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 4.38 minutes, [M+H]+ 758.
b) The tris-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired mono-guanidine as the tris- trifluoroacetate. LC retention time 2.90 minutes, [M+H]+ 458.
Example 22
Figure imgf000029_0001
As example 21 using 4-N,N'-bis-t-butoxycarbonylguanidinoaminomethylaniline. LC retention time 2.82 minutes, [M+H]+ 444.
Example 23.
Figure imgf000029_0002
As example 21 using l-amino-4-[(N,N'-bis-t-butoxycarbonyl)-N-methyl] guanidinobutane. LC retention time 2.78 minutes, [M+H]+ 424.
Example 24
Figure imgf000029_0003
As example 21 using mono-.Y-t-butoxycarbonyldiaminobutane. LC retention time 2.74 minutes. [M÷Hf 368. Example 25
Figure imgf000030_0001
To a mixture of the aldehyde of example 10 (1 eq.), dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2CO3 was added benzo[b]thiophene-2-boronic acid (2 eq) in dry, degassed DME and the mixture heated at 80°C for 16h. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS04. Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane. LC retention time 5.30 minutes, [M^H-Boc]"" 312.
Example 26
Figure imgf000030_0002
a)
Figure imgf000030_0003
The aldehyde (1 eq.) from Example 25 and mono-N,N'-bis-t-butoxycarbonylguanidino-m- xylenediamine (2 eq.) were stirred at RT for 15min in 1.2-dichloroethane. then sodium triacetoxyborohydride (1.5 eq.) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by cliromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 4.50 minutes, [M+H]' 760.
b) The tris-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired mono-guanidine as the tris- trifluoroacetate. LC retention time 2.90 minutes, [M+H]" 460.
Example 27
Figure imgf000031_0001
As example 26 using 4-N,N'-bis-t-butoxycarbonylguanidinoaminomethylaniline. LC retention time 2.90 minutes, [M+H]+ 460.
Example 28.
Figure imgf000031_0002
As example 26 using 4-aminomethylpyridine. LC retention time 3.09 minutes, [M+H]+ 404.
Example 29.
Figure imgf000031_0003
As example 26 using 2-(2-aminoethyl)pvridine. LC retention time 3.19 minutes. [M+H]" 418.
Example 30.
Figure imgf000032_0001
As example 26 using l-(3-aminopropyl)imidazole. LC retention time 2.87 minutes, [M+H]+ 421.
Example 31.
Figure imgf000032_0002
As example 26 using l-(3-aminopropyl)morpholine. LC retention time 2.86 minutes, [M+H]+ 440.
Example 32.
Figure imgf000032_0003
As example 26 using 5-(2-aminoethyl)imidazole. LC retention time 2.86 minutes, [M+H]+ 407.
Example 32.
Figure imgf000032_0004
As example 26 using .V.Λ-1.3-diaminopropane. LC retention time 2.84 minutes. [M-H]~ 398. Example 33.
Figure imgf000033_0001
As example 26 using 4-aminomethylbenzenesulfonamide. LC retention time 3.15 minutes. [M+H]" 482.
Example 34.
Figure imgf000033_0002
As example 26 using mono-NN'-bis-Boc-piperazine carboxamidine. LC retention time 2.92 minutes, [M+H]+ 424.
Example 35.
Figure imgf000033_0003
As example 26 using mono-.V,N'-bis-Boc-homopiperazine carboxamidine. LC retention time 2.83 minutes. [M+H]" 438.
Example 36.
Figure imgf000033_0004
J J
As example 26 using 5-aminomethyl-2-N-Boc-aminobenzimidazole. LC retention time 2.89 minutes, [M+H]" 458.
Example 37.
Figure imgf000034_0001
As example 26 using l-(3-aminopropyl)-2-methylpiperidine. LC retention time 2.93 minutes, [M+H]+ 452.
Example 38.
Figure imgf000034_0002
As example 26 using l-(2-aminoethyl)pyrrolidine. LC retention time 2.90 minutes, [M+H]+ 410.
Example 39.
Figure imgf000034_0003
As example 26 using 4-(2-aminoethyl)benzene sulfonamide. LC retention time 3.18 minutes, [M+H]+ 496.2
Example 40.
Figure imgf000034_0004
As example 26 using .V.N-dimethyl-1.2-diaminoethane. LC retention time 2.89 minutes. [M+H]" 384. Example 41.
Figure imgf000035_0001
As example 26 using tryptamine. LC retention time 3.36 minutes, [M+H]+ 456.
Example 42.
Figure imgf000035_0002
As example 26 using l-(2-aminoethyl)-4-N-Boc-piperazine. LC retention time 2.83 minutes, [M+H]+ 425.
Example 43.
Figure imgf000035_0003
As example 26 using l-(3-aminopropyl)-4-methylpiperazine. LC retention time 2.86 minutes, [M+H]+ 453.
Example 44.
Figure imgf000035_0004
As example 26 using l-(3-aminopropyl)pyrrolidine. LC retention time 2.87 minutes. [M+H]" 424. 33
Example 45.
Figure imgf000036_0001
As example 26 using 2-aminoethyl-l-ethylpyrrolidine. LC retention time 2.95 minutes, [M+H]+ 424.
Example 46.
Figure imgf000036_0002
As example 26 using N,N-diethyl-l,3-diaminopropane. LC retention time 2.88 minutes, [M+H]+ 426.
Example 47.
Figure imgf000036_0003
As example 26 using 4-aminomethyl-N,N-dimethylaniline. LC retention time 3.34 minutes, [M+H]+ 446.
Example 48.
Figure imgf000036_0004
As example 26 using .V..Y-dimethyl-2.2-dimeth l-1.3-diaminopropane. LC retention time 2.93 minutes. [M-t-H]" 426. Example 49.
Figure imgf000037_0001
As example 26 using l-(3-aminopropyl)pyrrolidinone. LC retention time 3.12 minutes, [M+H]+ 438.
Example 50.
Figure imgf000037_0002
As example 26 using 4-N-Boc-piperazine glycinamide. LC retention time 2.82 minutes, [M+H]+ 439.
Example 51.
Figure imgf000037_0003
As example 26 using 4-aminomethyl-l-iV-Boc-piperidine. LC retention time 2.93 minutes. [M+H]+ 410.
Example 5.'
Figure imgf000037_0004
COΛle As example 26 using δ-Ar-Boc-D.L-lysine methyl ester. LC retention time 2.94 minutes, [M+H]+ 456.
Example 53.
Figure imgf000038_0001
As example 26 using 3-aminomethylpyridine. LC retention time 2.93 minutes. [M+H]+ 404.
Example 54.
Figure imgf000038_0002
As example 26 using 4-(2-aminoethyl)-N-Boc-piperidine. LC retention time 2.87 minutes, [M+H]+ 424.
Example 55.
Figure imgf000038_0003
As example 26 using 4-(2-aminoethyl)pyridine. LC retention time 2.99 minutes, [M+H]+ 418.
Example 56.
Figure imgf000038_0004
As example 26 using bis-(2-Ar-Boc-aminoethyl)amine. LC retention time 0.62 minutes, [M+H]* 427.
Example 57
Figure imgf000039_0001
To a mixture of the aldehyde (1 eq) of example 10, dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na C03 was added l-N-t-butoxycarbonylindoline-5- boronic acid (2 eq) in dry. degassed DME and the mixture heated at 80°C for lh. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane. LC retention time 5.23 minutes, [M+H-Boc]+ 397.
Example 58
Figure imgf000039_0002
a)
Figure imgf000039_0003
The aldehyde (1 eq) from example 57 and l-(3-aminopropyl)-2-methylpiperidine ( 1.6 ) were stirred at RT for 15min in 1.2-dichloroethane. then sodium triacetoxyborohydride (1.5) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 3.47 minutes, [M+H]+ 637.
b) The bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for 10 min. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 0.58 minutes, [M+H]+ 437.
Example 59
Figure imgf000040_0001
As example 58 using N,N-diethyldiaminopropane. LC retention time 0.52 and 0.84 minutes, [M+H]+ 411.
Example 60
Figure imgf000040_0002
As example 58 using l-(3-aminopropyl)pyrrolidinone. LC retention time 0.56 and 2.60 minutes, [M+H]" 423.
Example 61
._- ___ ,0. /\ ,\H As example 58 using l -(3-aminopropyl)imidazole. LC retention time 0.54 and 0.78 minutes, [M-÷-H]+ 406.
Example 62
Figure imgf000041_0001
As example 58 using 4-(2-aminoefhyl)pyridine. LC retention time 0.57 minutes, [M+H]+ 403.
Example 63
Figure imgf000041_0002
To a mixture of the aldehyde (1 eq) of example 10, dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2C03 was added l-V-t-butoxycarbonyl-7- nitroindoline-5-boronic acid (2 eq) in dry, degassed DME and the mixture heated at 80°C for lh. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and w-ater. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane. LC retention time 5.03 minutes. [M+H-Boc]" 442. Example 64
Figure imgf000042_0001
a)
Figure imgf000042_0002
The aldehyde (1 eq) from example 63 and l-(3-aminopropyl)-2-methylpiperidine (1.6 eq) were stirred at RT for 15min in 1 ,2-dichloroethane, then sodium triacetoxyborohydride (1.5 eq) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol.
LC retention time 4.10 minutes. [M+H]+ 754.
b) The bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate.
LC retention time 2.84 minutes. [M+H]+ 482.
Example 65
Figure imgf000042_0003
As example 64 using l-(3-aminopropyl)imidazole. LC retention time 2.82 minutes, [M+H]+ 451.
Example 66
Figure imgf000043_0001
As example 64 using 4-(2-aminoethyl)-l-N-Boc-piperidine. LC retention time 2.81 minutes. [M+H]+ 454.
Example 67
Figure imgf000043_0002
To a mixture of the aldehyde (1 eq) of example 10, dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2CU3 was added l-N-t-butoxycarbonyl-7-nitroindole- 5-boronic acid in (2 eq) dry, degassed DME and the mixture heated at 80°C for lh. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane. LC retention time 5.20 minutes, [M+H-Boc]+ 440.
Example 68
Figure imgf000043_0003
a)
Figure imgf000044_0001
The aldehyde (1 eq) from example 67 and l-(3-aminopropyl)-2-methylpiperidine (1.6 eq) were stirred at RT for 15min in 1 ,2-dichloroethane, then sodium triacetoxyborohydride (1.5 eq) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 3.50 minutes, [M+H]+ 680.
b) The bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for 10 min. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 2.88 minutes, [M+H]+ 480.
Example 69
Figure imgf000044_0002
As example 68 using l-(3-aminopropyl)imidazole. LC retention time 2.84 minutes. [M+H]" 449.
Example 70
Figure imgf000045_0001
As example 68 using 4-(2-aminoethyl)-lN-t-butoxycarbonylpiperidine. LC retention time 2.85 minutes, [M+H]+ 452.
Example 71
Figure imgf000045_0002
As example 68 using 4-(2-aminoethyl)pyridine. LC retention time 2.95 minutes, [M+H]+ 446.
Example 72
Figure imgf000045_0003
a)
Figure imgf000045_0004
To a mixture of the aldehyde (1 eq) of example 10. dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2Cθ was added phenylboronic acid (2 eq) in dry. degassed DME and the mixture heated at 80ύC for 16h. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane.
LC retention time 4.81 minutes, [M+Na]+ 378.
b)
The aldehyde (1 eq) and mono-Λ"Λr'-bis-t-butoxycarbonylpiperazinecarboxamidine (1.6) were stirred at RT for 15min in 1.2-dichloroethane, then sodium triacetoxyborohydride (1.5) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of hexane and ethyl acetate. LC retention time 4.03 minutes, [M+H]+ 668.
c) The tris-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 0.52 and 2.57 minutes, [M+H]+ 368.
Example 73
Figure imgf000046_0002
As example 72 using jo-tolylboronic acid. LC retention time 2.71 minutes, [M+H]+ 382.
Example 74
Figure imgf000047_0001
As example 72 using 4-methoxyphenylboronic acid. LC retention time 2.64 minutes, [M+H]+ 398.
Example 75
Figure imgf000047_0002
As example 72 using 4-fluorophenylboronic acid. LC retention time 2.63 minutes, [M+H]+ 386.
Example 76
Figure imgf000047_0003
As example 72 using 3-trilluoromethylphenyiboronic acid. LC retention time 2.86 minutes. [MHH]" 436. Example 77
Figure imgf000048_0001
As example 72 using 3-thienylboronic acid.
LC retention time 0.51 and 2.50 minutes. [M^H]+ 374.
Example 78
Figure imgf000048_0002
a)
Figure imgf000048_0003
To a mixture of the aldehyde (1 eq) of example 10, dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2Cθ3 was added phenylboronic acid (2 eq) in dry. degassed DME and the mixture heated at 80°C for 16h. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethv 1 acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid. which was purified by cliromatography on silica gel eluting with mixtures of ethv 1 acetate and hexane. LC retention time 4.81 minutes. [M+Na]~ 378. b)
Figure imgf000049_0001
The aldehyde (1 eq) and mono-N,Λr'-bis-t-butoxycarbonylhomopiperazinecarboxamidine (1.6 eq) were stirred at RT for 15min in 1 ,2-dichloroethane. then sodium triacetoxyborohydride (1.5 eq) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by cliromatography on silica gel eluting with mixtures of hexane and ethyl acetate. LC retention time 4.03 minutes, [M+H]+ 668.
c) The tris-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 0.50 and 2.46 minutes, [M+H]" 382.
Figure imgf000049_0002
As example 78 using -tolviboronic acid. LC retention time 2.65 minutes. [M~H]" 396. Example 80
Figure imgf000050_0001
As example 78 using 4-methoxyphenylboronic acid. LC retention time 0.53 and 2.59 minutes, [M+H]+ 412.
Example 81
Figure imgf000050_0002
As example 78 using 4-fluorophenylboronic acid. LC retention time 0.54 and 2.56 minutes, [M+H]+ 400.
Example 82
Figure imgf000050_0003
As example 78 using 3-trifluoromethylphenylboronic acid. LC retention time 2.78 minutes. [M+H]" 450.
Example 83
Figure imgf000051_0001
As example 78 using 3-thienylboronic acid.
LC retention time 0.50 and 2.10 minutes, [M+H]" 388.
Figure imgf000051_0002
Reagents: (i) R"NH2, DCE, sodium triacetoxyborohydride; (ii) Di-t-butyl dicarbonate.
DCM, (i-Pr)2NEt; (iii) Bis(pinacolato)diboron, DMSO. KOAc, PdCl2 (dppf)2: (iv) Arylboronic acid. DMF. K3P04, PdCl2 (dppf)2; (v) TFA/DCM, 1/1. Scheme 4
The following examples were synthesized following the procedure outlined in Scheme 4.
Example 84
Figure imgf000051_0003
a)
Figure imgf000052_0001
The aldehyde (leq.) from example 10 and 4-(aminomethyl)-l-Boc-piperidine (l .όeq.) were stirred at RT for 15min in 1,2-dichloroethane. then sodium triacetoxyborohydride (1.5eq.) was added in one portion. After stirring for 16 hours at RT the mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was dissolved in DCM and diisopropylethylamine (leq.) and di-t-butyl dicarbonate (3eq.) added. The reaction was stirred at RT for lh, diluted with water and the organic layer separated and washed with brine. Drying (MgS0 ) and concentration in vacuo gave a solid, which was purified by chromatography on silica gel eluting with ethyl acetate/hexane mixtures. LC retention time 5.41minutes, [M-Boc+H]" 556.
b) The bromophenyl compound (leq.), bis(pinacolato)diboron (l .leq.) and potassium acetate (3eq.) in DMSO were treated with bis(diphenylphosphino)ferrocene palladium dichloride (lOmol %) and heated at 80°C for 3h. After this time, the solvents were partitioned between water and diethylether. the organic layer dried with MgS0 and finally concentrated. The oil produced was purified using chromatography on silica gel using ethyl acetate/hexanes.
LC retention time 5.45minutes, [M-Boc+H]" 604.
Example 85
Figure imgf000052_0002
a)
Figure imgf000052_0003
The boronate ester (leq.) from example 84 was treated with 5-bromo-l -N-Boc-indole (1.5eq.), potassium phosphate (3eq.) and bis(diphenylphosphino)ferrocene palladium dichloride (10 mol%) in DMF at 60°C for 4h. The mixture was filtered through celite and concentrated in vacuo. The residue was partitioned between between EtOAc and water, the organic layer was washed with brine and dried (MgS0 ). Concentration gave a residue which was purified by column chromatography on silica eluting with ethyl acetate/hexane mixtures. LC retention time 5.87 minutes, [M-Boc+H]+ 694.
b)The fully protected compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lOmin. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 2.68 minutes, [M+H]+ 392.
Example 86
Figure imgf000053_0001
As example 85 using 5-bromobenzofuran-2-methylamide. LC retention time 2.67 minutes, [M+H] 451.
Example 87
Figure imgf000053_0002
As example 85 using 2-bromopyridine. LC retention time 0.45 minutes. [M+H]" 355. Example 88
Figure imgf000054_0001
As example 85 using 5-bromoindan-2-one. LC retention time 3.09 minutes, [M+H]+ 408.
Example 89
Figure imgf000054_0002
As example 85 using 3-bromo(4'-fluoro)diphenylether. LC retention time 3.24 minutes, [M+H]+ 464.
Example 90
Figure imgf000054_0003
As example 85 using 5-bromochromanone. LC retention time 3.10 minutes, [M+H]+ 422.
Example 91
Figure imgf000054_0004
As example 85 using 3-bromoquinoline.
LC retention time 3.09 minutes. [M+H]' 405.
Example 92
Figure imgf000055_0001
As example 85 using bromobenzene.
LC retention time 0.49 minutes, [M+H]+ 354.
Example 93
Figure imgf000055_0002
As example 85 using 6-bromoquinaldine. LC retention time 0.47 minutes, [M+H]+ 419.
Example 94
Figure imgf000055_0003
As example 85 using 5-bromo-2,4-dimethoxypyrimidine. LC retention time 3.07 minutes, [M+H]+ 416.
Example 95
Figure imgf000055_0004
As example 85 using 5-bromoindole-2-methylamide. LC retention time 3.22 minutes. [M+H]" 450. Example 96
Figure imgf000056_0001
As example 85 using 5-bromoindole-2-benzv amide. LC retention time 1.11 minutes, [M+H]- 526.
Example 97
Figure imgf000056_0002
a)
Figure imgf000056_0003
The aldehyde (leq.) from example 10 and 4-(2-aminomethyl)-l-Boc-piperazine (1.5eq.) were stirred at RT for 15min in 1.2-dichloroethane, then sodium triacetoxyborohydride (1.5eq.) was added in one portion. After stirring 16 hours at RT the mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid which was dissolved in DCM, and diisopropylethylamine (5eq) and di-t-butyl dicarbonate (2eq.) added. The reaction was stirred at RT for lh. diluted with water and the organic layer separated and washed with brine. Drying (MgS0 ) and concentration in vacuo gave a solid which was purified by chromatography on silica gel eluting with ethyl acetate/hexane mixtures. LC retention time 4.25 minutes. [M+H]' 673. b) The bromophenyl compound (leq.). bis(pinacolato)diboron (l . leq.) and potassium acetate (3eq.) in DMSO were treated with bis(diphenylphosphino)ferrocene palladium dichloride (10 mol%) and heated at 80°C for 3h. After this time, the solvents were partitioned between water and diethylether, the organic layer dried with MgS04 and finally concentrated. The oil produced was purified using chromatography on silica gel using ethyl acetate/hexanes. LC retention time 4.27 minutes. [M+H]+ 719.
Example 98
Figure imgf000057_0001
a)
Figure imgf000057_0002
The boronate ester (leq.) from example 97 was treated with 5-bromo-l-Boc-indole (1.5eq.). potassium phosphate (3eq.) and with bis(diphenylphosphino)ferrocene palladium dichloride (10 mol%) in DMF at 60°C for h. The mixture was filtered through celite and concentrated in vacuo. The residue was partitioned between between EtOAc and water, the organic layer was washed with brine and dried (MgS04). Concentration gave a residue which was purified by column chromatography on silica gel eluting with ethyl acetate/hexane mixtures. LC retention time 4.79 minutes. [M-t-H]" 808.
b) The fully protected compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lOmin. The volatiles were removed in vacuo to give the desired compound as the tris-trifluoroacetate. LC retention time 2.70 minutes, [M-rH]" 408.
Example 99
Figure imgf000058_0001
As example 98 using 5-bromo-2,4-dimethoxypyrirnidine. LC retention time 1.03 minutes, [M+H]+ 431.
Example 100
Figure imgf000058_0002
As example 98 using 1.2,3,4-tetrahydro-9-Boc-6-bromocarbazole. LC retention time 3.21 minutes. [M+H]+ 462.
Figure imgf000059_0001
Figure imgf000059_0002
Reagents: (i) 3-bromo-l-phthalamidopropane, CS2CO3, DMF; (ii) 2- Benzo[b]thiopheneboronic acid, DME, K2CO3; (iii) (a) (iY,N'-bis- butoxycarbonyl)ΝH(CH2)4ΝH2, DCE. sodium triacetoxyborohydride, (b) di-t-butyl dicarbonate, DCM, (i-Pr)2NEt; (iv) hydrazine.hydrate, ; (v) RS02C1, Et3N, DCM; (vi) RCOC1, Et3N. CH3CN; (vii) RC1 (R=heterocycle), (i-Pr)2NEt, ; (viii) TFA/DCM, 1/1.
Scheme 5
The following examples were synthesized following the procedure outlined in Scheme 5.
Example 101.
Figure imgf000059_0003
\H, a)
Figure imgf000060_0001
5-Bromosalicylaldehyde (1 eq.) and cesium carbonate (2 eq.) were stirred in DMF and 3- bromo-1-phthalamidopropane (1.2 eq.) was added. After stirring for 18 hours at room temperature the reaction was concentrated in vacuo. The residue was partitioned between EtOAc and water and the organic la er washed with brine. Drying (MgS04) and concentration gave a residue which was purified by column chromatography on silica eluting with EtOAc/hexane to yield the protected amine. LC retention time 4.69 minutes. [M]" 388.
b)
Figure imgf000060_0002
To the aldehyde (1 eq.). 2N K2CO3 and benzo[b]thiophene-2-boronic acid (2 eq.) in dry, degassed DME was added dichlorobis(triphenylphosphine)palladium (0.1 eq.). and the mixture heated at 80°C for 18 h. After this time the reaction mixture was filtered, concentrated in vacuo. re-dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. The organic extract was dried (MgS0 ). filtered and concentrated in vacuo. LC retention time 5.24 minutes, [M+H]" 442.
c)
Figure imgf000060_0003
Bo^\H The aldehyde ( 1 eq.) and l-amino-4-Λ'r.Λτ '-bis-Boc-guanidinobutane ( 1.5 eq.) were stirred at RT for 15min in 1.2-dichloroethane, then sodium triacetoxyborohydride (1.5 eq.) was added in one portion. After stirring for 18 hours at RT the mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic layer was washed with brine and dried over MgSO4. Concentration gave a solid which was dissolved in DCM and treated with diisopropylethylamine (2 eq.) and di-t-butyl dicarbonate (2 eq.). After stirring for 4h at RT the reaction was diluted with water, the organic layer was washed with brine, and dried over MgS04. Concentration gave a solid which was purified by chromatography on silica gel eluting with 4: 1 hexane:ethyl acetate, then 2: 1 hexane:ethyl acetate
LC retention time 5.95 minutes. [M+H]+ 856.4
d)
Figure imgf000061_0001
The N-protected phthalimide (1 eq.) was treated with hydrazine hydrate (15 eq.) in EtOH for 18 h then concentrated in vacuo keeping the water bath below 40°C. The residue was dissolved in EtOAc and the organic layer washed exhaustively with water and finally with brine. The organic fraction was dried (MgS04), concentrated in vacuo and purified by column chromatography on silica, eluting with 75%EtOAc/hexane. then 5%MeOH/DCM.
e) The amine (1 eq.) and triethylamine (5 eq.) in acetonitrile was treated with methanesulfonyl chloride (3 eq.). After 2h at RT the reaction was diluted with water and the organic layer separated, washed with brine and dried (MgS0 ). Concentration gave an oil which was purified by column chromatography on silica, eluting with 1 : 1 EtOAc/hexane to yield the desired methane sulfonate.
The bis-Boc compound was treated with 1 mL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired mono-guanidine as the bis- trifluoroacetate.
LC retention time 3.1 minutes. [M-H]~ 504. Example 102.
Figure imgf000062_0001
NH,
As example 101 using benzenesulfonyl chloride. LC retention time 3.35 minutes, [M+H]+ 566.
Example 10
Figure imgf000062_0002
As example 101 using acetyl chloride.
LC retention time 3.12 minutes, [M+H]+ 468.
Example 104.
Figure imgf000062_0003
As example 101 using 2-chloro-4.6-dimethoxytriazine. LC retention time 3.24 minutes. [M+Hf 565. Example 105.
Figure imgf000063_0001
As example 101 using 2-chloro-4-trifluoromethylpyrimidine. LC retention time 3.45 minutes, [M+H]" 518.
Figure imgf000063_0002
Reagents: (i) Bis(pinacolato)diboron. KOAc, DMSO. PdCl (dppf)2; (ii) Arylboronic acid. DMF, K3P04. PdCl2 (dppf)2; (iii) (N.N"-bis-t-butoxycarbonyl)NH(CH2)3CH2NH2. DCE. sodium triacetoxyborohydride; (iv) TFA DCM, 1/1.
Scheme 6
The following examples were synthesized following the procedure outlined in Scheme 6.
Example 106
Figure imgf000063_0003
The aldehyde (leq.) from example 10. bis(pinacolato)diboron ( l . l eq. ) and potassium acetate (3eq.) in DMSO were treated with bis(diphen lphosphino)ferrocene palladium dichloride (10 mol%) and heated at 80°C for 3h. After this time, the solvents were partitioned between water and diethylether, the organic lav er dried with MgSO4 and finally concentrated. The oil produced was purified using chromatography on silica gel using ethyl acetate/hexanes. LC retention time 4.81 minutes. [M-Boc+H]' 306.
Example 107
Figure imgf000064_0001
NH,
a)
Figure imgf000064_0002
The boronate ester (leq.) from example 106 was treated with 5-bromobenzofuran-2- methylamide (1.5eq.), potassium phosphate (3eq.) and bis(diphenylphosphino)ferrocene palladium dichloride (10 mol%) in DMF at 60°C for 3h. The mixture was filtered through celite and concentrated in vacuo. The residue was partitioned between between EtOAc and water, the organic layer was washed with brine and dried (MgS04). Concentration gave a residue which was purified by column chromatography on silica eluting with ethyl acetate/hexane mixtures. LC retention time 4.89 minutes. [M-Boc+H]" 429.
b) z- υ^.. ^ . NHBoc
MeHNOC — 1 u ^- "- ^- The aldehyde ( leq.) and l -amino-4-(N.N"bis-Boc-guanidino)butane (1.5eq. ) were stin-ed at RT for 15min in dichloroethane. then sodium triacetoxyborohydride ( 1.5eq. ) was added in one portion. After stirring 16 hours at RT the mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic layer was washed with brine and dried over MgSO4. Concentration gave a solid which was purified by chromatography on silica gel eluting with ethyl acetate/hexane mixtures. LC retention time 4.40 minutes. [M-Boc+H]" 667.
c) The tris-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for lh. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 3.17 minutes, [M-H]" 467.
Example 108
Figure imgf000065_0001
As example 107 using 5-bromobenzofuran-2-benzylamide. LC retention time 3.19 minutes. [M-rH]+ 543.
Example 109
Figure imgf000065_0002
As example 107 using l-bromo-2.3-dimethoxybenzene. LC retention time 3.10 minutes. [M-H]" 430. Example 1 10
Figure imgf000066_0001
As example 107 using 2-bromothiazole. LC retention time 1.06 minutes, [M+H]' 377.
Example 111
Figure imgf000066_0002
As example 107 using 3-bromoquinoline. LC retention time 3.13 minutes, [M+H]" 421.
Example 112
Figure imgf000066_0003
As example 107 using 5-bromo-l-butoxycarbonylindole. LC retention time 3.13 minutes. [M+H]+ 409.
Example 113
Figure imgf000066_0004
As example 107 using 5-bromo-l-methylindole. LC retention time 2.77 minutes. [M-Hf 423.
Figure imgf000067_0001
Reagents: (i) BnBr. Cs2C03. DMF ; (ii) ArB(OH)2. DME. K C0 . PdCl2(PPh3)2 : (iii ) BCl3-SMe2. DCM; (iv) R,R2NH, MeOH-CH2Cl2 (1 : 1 v/v). Amberiyst A-26 borohvdride resin; (v) Boc20. DIPEA, MeCN: (vi) EtOH. Cs2C03. then R3X, DMF.
Scheme 7
The following examples were synthesised following the procedure outlined in scheme 7.
Example 114.
Figure imgf000067_0002
Figure imgf000067_0003
To 5-bromosalicaldehyde (1 eq.) and CS2CO3 (2 eq.) in DMF was added benzyl bromide ( 1.1 eq.). and the solution stirred under nitrogen for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The organic fraction was washed with water and saturated sodium chloride solution, dried (MgS0 ). filtered and concentrated in vacuo to give the benzv 1 ether as a white solid. b)
To the aryl bromide (1 eq.), 2N K2CO3 and benzo[b]thiophene-2-boronic acid (2 eq.) in dry. degassed DME was added dichlorobis(triphenylphosphine)palladium(II) (0.1 eq.) and the mixture heated at 80°C for 45 hours. After this time the reaction mixture was filtered, concentrated in vacuo, re-dissolved in ethyl acetate and washed with w ater and saturated sodium chloride solution. The organic extract was dried (MgSOj). filtered and concentrated in vacuo. LC retention time 5.47 minutes. [M+H]" 345.
c) The bisaryl (example 114b. 1 eq.) and boron trichloride-methyl sulfide complex (2 eq.) were stirred in dichloromethane for one hour. Saturated sodium bicarbonate was added and the organics collected. After passing through a short pad of silica and concentration under reduced pressure, the product was suspended in methanol-dichloromethane (1 :1 v/v) and shaken with 4-(aminomethyl)piperidine (1 eq.). After one hour, borohvdride (solid supported upon Amberiyst A-26 resin. 1.1 eq.) was added and shaking continued for 18 hours. After filtration, the solution was concentrated under reduced pressure, re-dissolved in acetonitrile and stirred for 18 hours with di-t-butyl dicarbonate (2 eq.) and di- isopropylethylamine (2 eq.). The resultant mixture was poured into water and extracted with eth l acetate. After concentration in vacuo, the compound was purified by chromatography- on silica gel, eluting with hexanes and ethyl acetate (4: 1 v/v) LC retention time 5.68 minutes.
Example 115
Figure imgf000068_0002
a)
Figure imgf000069_0001
The bisaryl (example 1 14. 1 eq.) and Cs2Cθ3 (2 eq.) in ethanol were heated to 80°C for one hour, and then concentrated to dryness. After re-suspension in DMF and w arming to 45°C under nitrogen, 3-(3-pyridyl)-l-bromopropane (1.5 eq.) was added and the suspension stirred for 18 hours. After concentration in vacuo, the compound was purified by chromatograph on silica gel. eluting with hexane:ethyl acetate (2: 1 w ). then dichloromethane:methanol (9:1 v/v).
b) The thus purified fully protected compound was treated with 1 mL of I T TFA/DCM and stirred at RT for 30 minutes. The volatiles were removed under reduced pressure to give the desired diamine as the tris-trifluoroacetate.
LC retention time 3.02 minutes. [M+H]" 472.
Example 116.
Figure imgf000069_0002
As example 1 15 using l-chloro-3-(N.N-dimethylamino)propane. LC retention time 3.02 minutes. [M+H]+ 438. Example 117.
Figure imgf000070_0001
As example 1 15 using 2-(2-chloroethyl)-l-methylpyrrolidine. LC retention time 3.00 minutes, [M+H]+ 464.
Example 1 18.
Figure imgf000070_0002
As example 115 using l-chloro-3-(N,N-dimethylamino)-2-methylpropane. LC retention time 3.16 minutes, [M+H]+ 452.
Example 119.
Figure imgf000070_0003
As example 115 using 4-(2-chloroethyl)morpholine. LC retention time 3.17 minutes. [M+H]" 466. Example 120.
Figure imgf000071_0001
As example 1 15 using N-(2-chloroethyl)pyrrolidine. LC retention time 3.16 minutes, [M+H]" 450.
Example 121.
Figure imgf000071_0002
As example 1 15 using 2-bromoethyl-N,N-diethylamine. LC retention time 3.20 minutes. [M+H]+ 452.
Example 122.
Figure imgf000071_0003
As example 1 15 using N-Boct-3-(bromomethyl)piperidine. LC retention time 3.24 minutes. [M+H]" 450. Example 123.
Figure imgf000072_0001
As example 1 15 using N-Boct-4-(2-bromoethyl)piperidine. LC retention time 3.24 minutes. [M+H]+ 464.
Example 124
Figure imgf000072_0002
As example 1 14 using N-(2-aminoethyl)piperidine. LC retention time 4.75 minutes. [M+H]+ 668.
Example 125.
Figure imgf000072_0003
a)
Figure imgf000072_0004
The bisaryl (example 124. 1 eq. ) and CS2CO3 (2 eq.j in ethanol were heated to 80°C for one hour, and then concentrated to dryness. After re-suspension in DMF and warming to 45°C under nitrogen. 3-(3-pyridyl)-l -bromopropane (1.5 eq.) was added and the suspension stirred for 18 hours. After concentration in vacuo, the compound was purified bv chromatography on silica gel. eluting with hexane:ethv l acetate (2: 1 v/v). then dichloromethane :methanol (9: 1 v v ).
b) The thus purified fully protected compound was treated with 1 mL of 1/1 TFA/DCM and stin-ed at RT for 30 minutes. The volatiles were removed under reduced pressure to give the desired triamine as the tetrakis-trifluoroacetate.
LC retention time 3.09 minutes. [M+H]" 487.
Example 126.
Figure imgf000073_0001
As example 125 using l-chloro-3-(N.N-dimethylamino)propane LC retention time 2.91 minutes. [M^-H]' 453.
Example 127.
Figure imgf000073_0002
As example 125 using 2-(2-chloroethv l)-l-methylpyrrolidine. LC retention time 2.97 minutes. [M-H]~ 479.
Example 128.
Figure imgf000074_0001
As example 125 using 2-bromoethyl-N.N-diethylamine. LC retention time 3.21 minutes, [M+H]" 467.
Example 129.
Figure imgf000074_0002
As example 125 using l-chloro-3-(N.N-dimethylamino)-2-methylpropane. LC retention time 3.21 minutes, [M+H]+467.
Example 130.
Figure imgf000074_0003
As example 125 using 2-picolyl chloride. LC retention time 3.30 minutes. [M+H]+ 459.
Example 131.
Figure imgf000074_0004
As example 125 using 3-picolyl chloride. LC retention time 3.27 minutes. [M+H]' 459.
Example 132.
Figure imgf000075_0001
As example 125 using 4-picolyl chloride. LC retention time 3.26 minutes. [M+H]~ 459.
Example 133.
Figure imgf000075_0002
As example 125 using 4-(2-chloroethyl)morpholine. LC retention time 3.18 minutes, [M+H]" 481.
Example 134.
Figure imgf000075_0003
As example 125 using 2-amino-6-(bromoethanoylamino)pyridine. LC retention time 3.34 minutes. [λTτ-H]~ 517.
Figure imgf000076_0001
Reagents: (i) N-Boc-bromopropylamine, Cs2CU3, DMF; (ii) 2-Benzo[b]thiopheneboronic acid, DME, PdCl2(PPh3)2, K2C03; (iii) (a) ΝH2OH.HCl, Et3N, 1,2-DCE. (b) H2, 10%Pd/C, MeOH, CHC13; (iv) (a) RC02H. HBTU. TEA. (b) TFA/DCM. 1/1.
Scheme 8
The following examples were synthesised following the procedure outlined in scheme 8.
Example 135.
Figure imgf000076_0002
a)
Figure imgf000076_0003
To 5-bromosalicaldehyde ( 1 eq. ) and Cs2CO (2 eq. ) in DMF was added Boc-3- bromopropylamine ( 1.2 eq.). and the solution stirred under nitrogen for 24 hours. The mixture as poured into water and extracted with ethyl acetate. The organic fraction was washed with water and saturated sodium chloride solution, dried and concentrated in vacuo to give the ether as a white solid. LC retention time 4.68 minutes. [M+H]" 380.
b)
Figure imgf000077_0001
To the aryl bromide (1 eq.). 2N K2CC>3 and benzo[b]thiophene-2-boronic acid (2 eq.) in dry, degassed DME was added dichlorobis(triphenylphosphine)palladium(II) (0.1 eq.) and the mixture heated at 80°C for 45 hours. After this time the reaction mixture was filtered, concentrated in vacuo. re-dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. The organic extract was dried (MgS0 ). filtered and concentrated in vacuo. LC retention time 5.19 minutes. [M-Boc'+H]" 298.
c) The aldehyde (1 eq.). hvdroxylamine hydrochloride (1.5 eq.) and triethylamine (2 eq.) were stirred for 18 hours in 1.2-dichloroethane. The mixture was then poured into dichloromethane and washed with brine. The organic fraction was dried, filtered and concentrated under reduced pressure. The resultant compound was re-dissolved in methanol, a few drops of chloroform were added, and the mixture stirred under a hydrogen atmosphere for 18 hours over 10% palladium on carbon (1 eq. by weight). After filtration through a short pad of celite. the volatiles were removed under reduced pressure to give the amine as the hydrochloride salt. LC retention time 3.75 minutes. [M-H]" 413.
Example 136.
Figure imgf000077_0002
a)
Figure imgf000078_0001
The amine from example 135. Boc-3-aminopropanoic acid (1 eq.). hydroxybenzotriazole (1.1 eq.) and triethylamine (5 eq.) were stin-ed together in DMF for 18 hours. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water and the organic layer dried (MgS04) and concentrated in vacuo. The residue was purified by column cliromatography on silica eluting with 75%EtOAc/hexane. LC retention time 5.05 minutes, [M+H]" 570.
b) The thus purified fully protected compound was treated with 1 mL of 1/1 TFA DCM and stirred at RT for 30 minutes. The volatiles were removed under reduced pressure to give the desired diamine as the bistrifluoroacetate.
Example 137.
Figure imgf000078_0002
As for example 136. using N-Boc-4-aminobutanoic acid.
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000079_0003
Reagents: (i) (a) TFA DCM, (b) 2-Nitro-phenylsulfonyl chloride, TEA. DCM; (ii) RX. Cs2C03, DMF; (iii) PhSH. DBU, CH3CN: (iv) Boc20. DIPEA, CH3CN; (v) l-amino-4- (N.N,-bis-Bocguanidino)butane, NaB(OAc)3H, 1,2-DCE; (vi)TFA/DCM, 1/1.
Scheme 9
The following examples were synthesised following the procedure outlined in scheme 9.
Example 138.
Figure imgf000079_0004
The aldehyde from example 25 ( 1 eq. ). was dissolved in 1 mL of 1/1 TFA DCM and stined at RT for 30 minutes. The volatiles were removed under reduced pressure to give the amine as the trifluoroacetate salt. This salt was re-dissolved in dichloromethane and stirred with 2-nitrophenylsulfonv 1 chloride (2 eq. ) and triethylamine ( 2 eq. ) for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic fraction was washed with water and saturated sodium chloride solution, dried (MgSO ) and concentrated under reduced pressure to give the sulfonamide as a white solid.
Example 139
Figure imgf000080_0001
a)
Figure imgf000080_0002
To the aldehyde from example 138 (1 eq.). and Cs2CC>3 (2 eq.) in DMF was added methyl iodide (2 eq.). and the solution stirred under nitrogen for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The organic fraction was washed with water and saturated sodium chloride solution, dried and concentrated under reduced pressure.
b)
Figure imgf000080_0003
The biaryl ( 1 eq.). DBU (5 eq.) and thiophenol (4 eq.) were stirred together in DMF for 2h hours. The mixture was concentrated in vacuo and partitioned between EtOAc and water, the organic lav er dried (MgS0 ) and concentrated in vacuo. The compound was then re- dissolved in acetonitrile and stirred for 18 hours with di-'butyl dicarbonate (2 eq. ) and di- isopropylethylamine (2 eq. ). The resultant mixture was poured into water and extracted with ethv l acetate. The organic fraction was dried (MgS0 ). filtered and concentrated in vacuo to giv e the desired compound.
c)
Figure imgf000081_0001
The aldehyde (1 eq.) and l-amino-4-(.YΛ~bis-Boc-guanidino)butane (1.5 eq.) were stirred at RT for 15min in dichloroethane. then sodium triacetoxyborohydride (1.5 eq. ) was added. After stining for 18 hours at RT the mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic layer was dried, filtered and concentrated in vacuo to giv e the crude product. This was purified bv column chromatography (silica, eluting with dichloromethane, then dichloromethane: methanol 95:5 v/v).
d) The thus purified fully protected compound was treated with 1 mL of 1/1 TFA/DCM and stirred at RT for 30 minutes. The olatiles were removed in vacuo to give the desired guanidine as the tris-trifluoroacetate.
LC retention time 2.88 minutes. [M+H]" 440.
Example 140.
Figure imgf000081_0002
As for example 139. using benzv l bromide. LC retention time 3.054 minutes. [M-H]" 516.25. Example 141
Figure imgf000082_0001
To a mixture of the aldehyde (1 eq) of example 10. dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2C0 was added 5-methoxyindole-2-boronic acid (2 eq) in dry. degassed DME and the mixture heated at 80°C for lh. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane. LC retention time 5.19 minutes, [M+H-Boc]+ 425.
Example 142
Figure imgf000082_0002
a)
Figure imgf000082_0003
The aldehyde ( 1 eq) from example 141 and N.N-Dimethylethv lenediamine ( 1.6 eq) were stirred at RT for 15min in 1.2-dichloroethane. then sodium triacetoxyborohydride ( 1.5) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacua and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which w as purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 3.65 minutes, [M+H]+ 567.
b) The bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for 10 min. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 2.81 minutes, [M+H]" 397.
Example 143
Figure imgf000083_0001
As example 142 using N,N-Diethylpropylenediamine. LC retention time 2.80 minutes, [M+H]+ 439.
Example 144
Figure imgf000083_0002
As example 142 using l-(3-Aminopropyl)-2-pipecoline. LC retention time 2.88 minutes. [M+H]+ 465. Example 145
Figure imgf000084_0001
As example 142 using l-(2-Aminoethyl)piperazine. LC retention time 2.82 minutes. [M-^H]" 438.
Example 146
Figure imgf000084_0002
As example 142 using l-(3-Aminopropyl)imidazole. LC retention time 2.78 minutes, [M+H]" 434.
Example 147
Figure imgf000084_0003
To a mixture of the aldehyde ( 1 eq) of example 10. dichlorobis(triphenylphosphine)- palladium(II) ( 10 mol%) and 2N Na CO3 was added 3-methylindole-2-boronic acid (2 eq) in dry. degassed DME and the mixture heated at 80°C for lh. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethv l acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethv l acetate and hexane. LC retention time 5.33 minutes. [M+H-Boc]" 409.
Example 148
Figure imgf000085_0001
a)
Figure imgf000085_0002
The aldehyde (1 eq) from example 147 and l-(3-Aminopropyl)-2-pipecoline (1.6 eq) were stirred at RT for 15min in 1,2-dichloroethane. then sodium triacetoxyborohydride (1.5) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 3.65 minutes, [M+H]" 649.
b) The bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for 10 min. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 2.94 minutes. [M-t-H]" 449.
Example 149
Figure imgf000085_0003
UN.. As example 148 using l-(2-Aminoethyl)piperazine. LC retention time 2.88 minutes. [M+H]+ 422.
Example 150
Figure imgf000086_0001
As example 148 using l-(2-Aminoethyl)piperidine. LC retention time 2.90 minutes, [M+H]+ 421.
Example 151
Figure imgf000086_0002
As example 148 using 4-(Aminomethyl)piperidine. LC retention time 3.58 minutes. [M+H]+ 406.
Example 152
Figure imgf000086_0003
To a mixture of the aldehyde ( 1 eq) of example 10. dichlorobis(triphenylphosphine )- palladium( II) ( 10 mol%) and 2N Na2Cθ was added 4-methylindole-2-boronic acid (2 eq) in drv. degassed DME and the mixture heated at 80ύC for lh. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethv l acetate and hexane. LC retention time 5.28 minutes. [M+H-Boc]" 409.
Example 153
Figure imgf000087_0001
a)
Figure imgf000087_0002
The aldehyde (1 eq) from example 152 and l-(3-Aminopropyl)-2-pipecoline (1.6 eq) were stirred at RT for 15min in 1.2-dichloroethane. then sodium triacetoxyborohydride (1.5 ) was added in one portion. After stirring for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 3.66 minutes, [M+H]" 649.
b) The bis-Boc compound w_as treated with lmL of 1/1 DCM/TFA and stirred at RT for 10 min. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate.
LC retention time 2.92 minutes. [M+H]" 449. Example 154
Figure imgf000088_0001
As example 153 using l-(2-Aminoethyl)piperazine. LC retention time 2.86 minutes. [M-*-H]+ 422.
Example 155
Figure imgf000088_0002
As example 153 using l-(2-Aminoethyl)piperidine. LC retention time 2.92 minutes. [M+H]+ 421.
Example 156
Figure imgf000088_0003
As example 153 using 4-(Aminomethyl)piperidine. LC retention time 2.91 minutes. [M-H]" 407. Example 157
Figure imgf000089_0001
To a mixture of the aldehyde (1 eq) of example 10. dichlorobis(triphenvlphosphine)- palladium(II) (10 mol%) and 2N Na2CU3 was added 6-chloroindole-2-boronic acid (2 eq) in dry. degassed DME and the mixture heated at 80°C for lh. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane. LC retention time 5.16 minutes, [M+H-Boc]+ 429.
Figure imgf000089_0002
Figure imgf000089_0003
Cl
The aldehyde ( 1 eq) from example 157 and l-(3-Aminopropv l)-2-pipecoline ( 1.6 eq) were stirred at RT for 15min in 1.2-dichloroethane. then sodium triacetoxv borohv dride ( 1.5 ) was added in one portion. After stimng for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic lav er was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 3.73 minutes, [M+H]" 669.
b) The bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for 10 min. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate. LC retention time 3.04 minutes. [M+H]÷ 469.
Example 159
Figure imgf000090_0001
As example 158 using l-(2-Aminoethyl)piperazine. LC retention time 2.97 minutes, [M+H]+ 442.
Example 160
Figure imgf000090_0002
As example 158 using l-(2-Aminoethyl)piperidine. LC retention time 2.99 minutes. [M+H]" 441. Example 161
Figure imgf000091_0001
As example 158 using 4-(Aminomethyl)piperidine. LC retention time 3.00 minutes, [M+H]+ 427.
Example 162
Figure imgf000091_0002
To a mixture of the aldehyde (1 eq) of example 10, dichlorobis(triphenylphosphine)- palladium(II) (10 mol%) and 2N Na2C03 was added 5-fluoroindole-2-boronic acid (2 eq) in dry, degassed DME and the mixture heated at 80°C for lh. After cooling to RT the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgS04. Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of ethyl acetate and hexane. LC retention time 5.31 minutes, [M+H-Boc]+ 413.
Example 163
Figure imgf000091_0003
.NH
N a)
Figure imgf000092_0001
The aldehyde (1 eq) from example 162 and N.N-Dimethylethylenediamine (1.6 eq) were stirred at RT for 15min in 1.2-dichloroethane. then sodium triacetoxyborohydride (1.5) was added in one portion. After stircing for 16h at RT the mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgS0 . Concentration gave a solid, which was purified by chromatography on silica gel eluting with mixtures of dichloromethane and methanol. LC retention time 3.59 minutes, [M+H]+ 585.
b) The bis-Boc compound was treated with lmL of 1/1 DCM/TFA and stirred at RT for 10 min. The volatiles were removed in vacuo to give the desired compound as the tris- trifluoroacetate.
LC retention time 2.96 minutes. [M+H]" 385.
Example 164
Figure imgf000092_0002
As example 163 using 4-(Aminomethyl)piperidine. LC retention time 2.89 minutes. [M-H]" 41 1. Example 165
Figure imgf000093_0001
As example 163 using l-(2-Aminoethyl)piperidine. LC retention time 2.93 minutes. [M+H]+ 425.
Example 166
Figure imgf000093_0002
As example 163 using l-(2-Aminoethyl)piperazine. LC retention time 2.85 minutes. [M+H]* 426.
Tat-Tar Binding Inhibition Assay
Principle of the assay
To measure the inhibition by the compound of RNA binding to ADP-1. the RNA is titrated in the presence of a constant amount of fluorescent donor (fluorescein- ADP-1 peptide) and compound as described in International Patent Application W099/64625. The assay is performed under competitive conditions, with a two fold excess of competitor RNA (a fully base-paired TAR sequence ) over fluorescein- ADP-1 peptide (the fluorescent donor). The TAR RNA contains a 3' dabcyl group. The dabcyl group is a non-fluorescent acceptor for energy transfer from tluorescein (the fluorescent donor). When ADP-1 and RNA bind, the fluorescence signal from the fluorescein is quenched by the close proximitv of the Dabcyl group. The presence of an inhibitory compound disrupts the ADP- 1 RNA complex. Complex disruption causes a decrease in energy transfer, which is observed as an increase in donor fluorescence intensity relative to a control (dabcyl) RNA-(fluorescein) ADP-1 binding reaction (in the absence of compound).
Disruption of DABCYL-TAR-FAM-ADP-1 complex formation by compounds of the invention.
Measurements were made in a 96-well plate reader (Wallac victor) with a fixed wavelength of 490nm and emission at 535 nm. Io vvas determined by an initial measurement of a 95 μL solution of l OnM Fluoresein-ADP-1 in the presence of 50mM Tris.HCl pH7.5, 80mM KC1 ,1% DMSO 0.01% Triton X-100. 5 μg/mL BSA . 20nM competitor RNA in the presence l μM compound. I was then measured following the addition of 5 uL of a 20 X DABCYL-TAR RNA stock solution.
Figure imgf000094_0001
Figure imgf000095_0001
In vitro Translation assay
Compounds of the present invention showed inhibitory activities in in vitro translation assays utilizing E. coli extracts. The plasmid pBestLuc. which contained the gene for firefly luciferase downstream of an E. coli promoter and a ribosome binding site was used as a template. The activity of the firefly luciferase enzyme resulted in a strong luminescent signal. The luminescence generated was a direct measurement of protein expression and of translation efficiencv.
Translation reactions in the presence of compound were started by mixing a translation premix that contained Mg~~. plasmid template, amino acids, nucleotidetriphosphates. phosphocreatine. creatine phosphokinase and folinic acid with the S30 extract that contains RNA polymerase. ribosomes and translation factors (prepared from E.coli MRΕ600 cells) followed bv incubation at 37°C. The activity of the translated luciferase protein was measured by adding an aliquot of the translation reaction to the non-luminescent substrate luciferin and the luminescence measured. The luminescence w as quantified in a luminescence plate reader (Wallac Victor). Compounds were assayed 3-5 times over a range of concentrations and an IC50 calculated.
Figure imgf000096_0001
In vivo antibacterial assay
The in vivo therapeutic efficacy of the compounds of the invention is measured by intramuscular injection to mice experimentally infected with a pathogenic gram positive or gram negative bacterium (e.g. methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile. Klebsiella pneumoniae. Eschericia coli, Haemophilus influenzae. etc.). As an example, MRSA strain A27223 can be used.
MRSA strain A27223 is prepared for experimental infection by growth on two large Brain Heart Infusion Agar plates. On each plate. 0.5 ml of frozen stock culture is plated out. Plates are then incubated for 18 hours at 30°C. The next day each plate is washed with 20 ml of Brain Heart Infusion Broth and then pooled together. A microscopic direct count of microorganisms is done using a 1 : 1000 dilution of plate wash. After a direct count is obtained, the number of organisms per milliliter is calculated. The count is adjusted to the desired amount of inoculum by diluting in 4% hog mucin. The desired challenge (amount of organisms given to mice) is 2.4 x 108 cfu/0.5 ml/mouse for MRSA strain A27223. The mice are infected intraperitoneally with 0.5 ml of challenge. Ten non-treated infected mice are used as controls. Mice used are adult male ICR mice. The average weight of the animals should range from 20 to about 26 grams.
Compounds are general tested at 4 dose lev els (e.g. 25. 6.25. 1 .56 and 0.39 mg kg) and prepared in 5% cremophor. unless otherw ise specified. When MRSA A27223 is the challenging microorganism, v ancomycin is used as the control compound, and is dosed at 6.25. 1.56, 0.39 and 0.098 mg/kg. It is prepared in 0.1M phosphate buffer. There are generally five infected mice per dose level, and they are treated with 0.2 ml of the test compound, preferably by intramuscular injection. Treatment begins 15 minutes and 2 hours post-infection.
A PD50 (protective dose-50. the dose of drug given which protects 50% mice from mortality) runs for 5 da s. During this time, mortality of mice is checked ev ery day and deaths are recorded. The cumulative mortality at each dose level is used to calculate a PD50 value for each compound. Surviving mice are sacrificed at the end of day 5 by C02 inhalation. The actual calculation of PD50 is performed with a computer program using the Spearman-Karber procedure.
A compound according to the invention is effective for the treatment of bacterial infection if it has a PD50 of about 100 mg/kg or less.
In vivo antiviral assav
The in vivo therapeutic efficacy of the compounds of the invention is measured by conventional in vivo antiviral assays including, but not limited to. that described in Letvin. N.L.. Daniel, M.D.. Sehgal. P.K., Desrosiers, R.C., Hunt. R.D.. Waldron. L.M.. MacKey. J.J.. Schmidt. D.K.. Chalifoux. L.V. and King. N.W. Introduction of AIDS-like disease in macaque monkeys with T-cell tropic retrovirus STLV-III. Science, 1985. 230. 71-73. which is incorporated herein by reference.
Variations, modifications, and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and scope of the invention as claimed. Accordingly, the invention is to be defined not by the preceding illustrative description but instead by the spirit and scope of the following claims.

Claims

CLAIMS:
1. A compound of the formula
Figure imgf000098_0001
wherein
Ar is an aryl group.
X1 is selected from O. S, SO. S02. and NR, X2 is selected from O. S, SO, S02. NR and CR2. X3 is CR2. Y1 and Y2 are independently selected from Cι-ι2 alkylene. C4_ι2 arylene, C .ι6 aralkylene. CO(Ci_i2 alkylene), CO(C _ι arylene) and CO(C _ι6 aralkylene) groups, A and B are independently selected from groups comprising a group selected from: amine (-NR2). amide (-CONR2). amidine (-C(=NR)NR2). thioamide
(-CSNR2), oxime (=NOR). hvdroxylamine (-NHOR). hydroxamic acid (-CONROR), hydrazine (-NRNR2). hvdrazone (=NNR2). sulphonamide
(-SO2NR2), sulphinamide (-SONR2), sulphoximine (-SO(=NR)-). urea
(-NRCONR2). guanidine (-NRC(=NR)NR2), and aromatic and non-aromatic nitrogen heterocyclic groups. each R is independently selected from H, C1-12 alkyl and C3_ι2 arvl, or any two R groups may together comprise a Cι-6 alkylene chain. or a pharmaceutically acceptable derivative thereof.
2. A compound according to claim 1 wherein X is O.
3. A compound according to claim 1 or 2 wherein X" is NR.
4. A compound according to claim 3 wherein X is NH.
5. A compound according to am preceding claim wherem X' is CH2
6. A compound according to any preceding claim wherein Ar is a monocyclic or a fused bicyclic aromatic or heteroaromatic group.
7. A compound according to claim 6 wherein Ar is a fused bicyclic heteroaromatic group of the formula
Figure imgf000099_0001
wherein X4 is NH, S or O.
8. A compound according to claim 7 wherein X is NH.
9. A compound according to any preceding claim wherein Y comprises a Cι-5 alkv lene group.
10. A compound according to any preceding claim wherein Y" comprises a C1.5 alkv lene group.
1 1. A compound according to any preceding claim wherein A is a group comprising a group selected from amine. amidine, guanidine. and aromatic and non-aromatic nitrogen heterocyclic groups.
12. A compound according to any preceding claim wherein B is a group comprising a group selected from amine. amidine, guanidine. and aromatic and non-aromatic nitrogen heterocyclic groups.
13. A compound according to any one of claims 1 to 12 for use in therapy.
14. Use of a compound according to any one of claims 1 to 12 in the manufacture of a medicament for use in the treatment of viral infection or bacterial infection.
15. A method of treating viral infection or bacterial infection comprising administering to a patient in need of such treatment an effective dose of a compound according to any one of claims 1 to 12.
16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 in combination with a pharmaceutically acceptable excipient.
17. Use of a compound according to any one of claims 1 to 12 to inhibit the binding of Tat to Tar or to inhibit bacterial protein translation.
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US8088768B2 (en) 2001-10-22 2012-01-03 The Research Foundation Of The State University Of New York Protein kinase and phosphatase inhibitors
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US8013006B2 (en) 2004-07-14 2011-09-06 Ptc Therapeutics, Inc. Methods for treating hepatitis C
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US7838542B2 (en) 2006-06-29 2010-11-23 Kinex Pharmaceuticals, Llc Bicyclic compositions and methods for modulating a kinase cascade
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