WO1997048705A1 - Potassium channel blockers - Google Patents

Potassium channel blockers Download PDF

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WO1997048705A1
WO1997048705A1 PCT/GB1997/001659 GB9701659W WO9748705A1 WO 1997048705 A1 WO1997048705 A1 WO 1997048705A1 GB 9701659 W GB9701659 W GB 9701659W WO 9748705 A1 WO9748705 A1 WO 9748705A1
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compound
mmol
bis
group
trifluoroacetate
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PCT/GB1997/001659
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French (fr)
Inventor
Joaquin Campos-Rosa
Philip Michael Dunn
Dimitrios Galanakis
Charon Robin Ganellin
Donald Hugh Jenkinson
Donglai Yang
Jianqing Chen
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University College London
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/18—Bridged systems

Definitions

  • the present invention relates to compounds having pharmaceutical (including veterinary) use, in particular compounds capable of blocking calcium activated potassium channels in human and other mammalian cells, to methods of making such compounds and to the use of such compounds in the treatment of various disorders.
  • Ca 2+ -activated K + channels are found in a wide variety of cell types and can be divided into three main classes on the basis of single channel conductance and sensitivity to blocking agents.
  • the SK Ca channel is characterized by its small single channel conductance (6-20 pS) and high sensitivity to the bee venom toxin apamin.
  • Estimates of the apamin concentration required to cause 50% block of SK Ca channels vary considerably between cells, ranging from 0.2 to 20 nM.
  • the action of apamin may reverse rapidly or very slowly, depending on the cell type. From these observations it might be inferred that subtypes of SK Ca channels exist .
  • An aim of the present invention is to provide compounds suitable for blocking SK Ca channels that are not peptides and are more potent than known compounds.
  • a further aim of the present invention is to provide compounds that exhibit selectivity in blocking SK Ca channels in different cells.
  • a first aspect of the present invention provides a compound having the general formula I or II:
  • each Q " is the conjugate base of a pharmaceutically acceptable inorganic or organic acid
  • Ri is selected from H and
  • R 5 being selected from H, and substituents such as a halogen, an alkyl group with 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group;
  • R 2 and R 3 are independently selected from H, and substituents such as a halogen, an alkyl group with 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group;
  • R 4 is selected from H and R c
  • R 6 being selected from H, and substituents such as a halogen, an alkyl group with 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group; where R 2 , R 3 , R 5 and R 6 may be present once or a plural number of times on the respective rings; each X is independently selected from NH, NR 7 , O, S and CH 2 , R 7 being selected from alkyl, aryl, alkaryl and aralkyl groups having 1 to 10 carbon atoms; A and B which are the same or different, are each selected from a spacing group with a chain length of 3 to 15 atoms; except that in general formula I when
  • R 2 and R 3 are H, X is NH, and A is (CH 2 ) 10 ,
  • the term "chain length" throughout this description and claims should be taken to mean the lowest number of atoms between one end of the spacing group and another.
  • the spacing group may contain rings, e.g. cycloalkyl and aromatic, including heterocyclic, substituted or unsubstituted.
  • the spacing groups may contain one or more O or S atoms as part of the chains.
  • the type of linkages possible with these atoms are for example an ether linkage (-0-) ,and thio linkages (-S-) and (-S-S-) . To avoid instability these linkages should not be adjacent to the N atoms of the pyridine or quinoline rings or to X if X is NH, O or S. Aditionally it is preferable that no methylene group has a hetero atom on both sides.
  • the preferred chain length is 3 to 10, more preferably 4 to 7.
  • X is NH, R 1 and R 4 are
  • R 2 ,R 3 ,R 5 and R 6 are not H, it may be any substituent which is pharmaceutically acceptable and which does not remove the potency of the molecule in the effects described herein, in particular the blocking of Ca 2+ -activated K + channels.
  • substituents are given above. Others are such as acyl, -CH, etc.
  • R 7 is selected from H, OH, OMe.
  • the two most potent compounds are where both A and B are -(CH 2 ) 5 - and where A is
  • These spacing groups have a chain length of 5 and 6 respectively.
  • the compounds of the present invention work as potassium channel blockers by the virtue that they exhibit the property of a relatively determined spatial relationship between the two pyridine or quinoline rings of the compound; the two spacing groups hold the two pyridine or quinoline rings in this spatial relationship. This relationship may not be obtained when only one spacing group is present between the two pyridine or quinoline rings since the conformation of the spacing group changes. It appears to the present inventors that the chain length between the two pyridine or quinoline rings affects the potency of the compound as a SK ca channel blocker. For these reasons, it is at present believed that the function of the spacing groups is primarily to provide a stable linkage between the two pyridine or quinoline rings, the chemical nature of these spacing groups being preferably relatively inert.
  • a second aspect of the present invention provides a method for producing a compound of the invention as described above having the general formula I, by reacting a compound of the general formula:
  • Y and Z are independently selected from a sulphonate
  • Z is selected from Cl, Br and I.
  • Y and Z are independently selected from CI, Br and I.
  • a third aspect of the present invention provides the use of compounds of the present invention in the treatment of any one of the following disorders: myotonic muscular dystrophy, gastrointestinal dysmotilities, disorders of memory, narcolepsy and associated disorders, cancers, ethanol-induced neurotoxicity and bacterial infection.
  • a fourth aspect of the present invention provides the use of compounds of the present invention in the preparation of a pharmaceutical for the treatment of any one of the following disorders: myotonic muscular dystrophy, gastrointestinal dysmotilities, disorders of memory, narcolepsy and associated disorders, cancers, ethanol-induced neurotoxicity and bacterial infection.
  • a fifth aspect of the present invention provides a pharmaceutical composition containing a compound of the present invention.
  • compositions provided may be administered to human individuals or used as a veterinary medicine, particularly for other mammals.
  • Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to a patient.
  • Such benefit may be at least amelioration of at least one symptom.
  • the actual amount administered, and rate and time- course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, eg decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors.
  • compositions according to the present invention may comprise, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous or intravenous.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, tonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, tonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • mp melting point, but where this is followed , by (dec) or (decomp) , it indicates decomposition at the temperature given.
  • bp is boiling point.
  • MeOH is CH 3 OH
  • EtOH is C 2 H 5 OH
  • DMF is dimethyl formamide
  • Groups A and B are detailed in Table 1 for each of Compounds 1 to 41.
  • 1,7(1,4) -diquinolinacyclotetradecaphane tri- trifluoroacetate trihydrate dimethanolate Alternatively named: 1, 1'- ⁇ [2,6-bis (4'- methylenephenyl)pyridine] -N 4 ,N 4 ' " (p,p' - dimethylenediphenylmethane) ⁇ -bis(4-aminoquinolinium) tri-trifluoroacetate trihydrate dimethanolate: 4,4 ' -bis [ (quinolin-4-yl) aminomethyl] diphenylmethane
  • N 4 '- (propane-1, 3-diyl) -bis- (4-aminoquinoline) 0.3 g, 0.914 mmol
  • 1, 4-diiodobutane 0.283 g, 0.914 mmol
  • 2-butanone 250 ml
  • N 4 , N 4 '- (Hexane-1, 6-diyl) -bis- (4-aminoquinoline) (0.5 g, 1.35 mmol) and 1, 3-di- (bromomethyl)benzene (0.36 g, 1.35 mmol) in 2-butanone (85 ml) were heated under reflux with stirring for 5 days and then cooled.
  • the resulting precipitate was collected, washed extensively with diethyl ether, and purified by preparative HPLC to give the product as a crystalline solid which was dried in vacuo at 40 °C for 3 days and had mp: 228-230 °C.
  • Ganglia were then dissociated using a fire-polished Pasteur pipette, and the resultant cell suspension plated onto laminin coated plastic culture dishes.
  • Cells were grown in L- 15 medium supplemented with 10% foetal calf serum, 0.2 mM glutamine, 0.6%(w/v) D-glucose, 0.19% (w/v) NaHC0 3 , penicillin (100 U ml "1 ) , streptomycin (100 ⁇ g ml "1 ) and nerve growth factor (mouse submaxillary gland 50 ng ml " x ) .
  • Cells were maintained at 37°C in an atmosphere of 95% 0 2 :5% C0 2 and are used between 6 hours and 10 days in culture.
  • a culture dish was perfused with a solution (hereafter referred to as normal physiological solution) of the following composition (mM) : NaCl 154; KCI 4.7; CaCl 2 2.5; MgCl 2 1.2; glucose 5.6; HEPES 10 (HEPES is N- (2- hydroxyethyl) piperazine-N' - (2-ethane sulfonic acid) ; adjusted to pH 7.4 with NaOH.
  • Intracellular recordings were made using conventional " *sharp' micro-electrodes filled with 1 M KCI (resistance 80-120 M ⁇ ) connected to the headstage of a Neurolog NL102 amplifier. Action potentials were evoked by injection of a 30 ms depolarizing current pulse every 5 s.
  • the test compounds as synthesised in the example above were applied by bath perfusion for long enough (1-3 min) to cause a steady reduction in the AHP. The extent of the inhibition is expressed as a percentage.
  • IC 50 value i.e. the concentration of compound required to produce an inhibition of 50%; this is determined by iterative curve fitting and has an associated standard deviation (s.d.) .
  • Dequalinium has previously shown to be a potent and selective inhibitor of the AHP in sympathetic neurones, with an IC 50 of 1 ⁇ M [Dunn, P.M (1994. Dequalinium, a selective blocker of the slow afterhyperpolarization in rat sympathetic neurones in culture. European Journal of Pharmacology, 252, 189-194] . In the present study it was slightly more effective with an average IC 50 of 0.60 ⁇ 0.05 ⁇ M (fitted value ⁇ s.d. data from 17 cells) , and dequalinium was used in each test as an internal standard. Compound A was found to be considerably more active than dequalinium with an IC S0 of 0.08 ⁇ 0.02 ⁇ M (fitted value ⁇ s.d. data from 12 cells) . Gallamine is over 100 times less potent than dequalinium, with an IC 50 of 68.0 + 8.4 ⁇ M (fitted value ⁇ s.d. data from 5 cells) .
  • 6-Iodo-N- (4-quinolinyl) -hexylamine A mixture of 6- (4-quinolinyl)aminohexan-1-ol (starting material E) (1.3 g, 5.3 mmol) and HI (2 ml, 57%) was heated at reflux for 2 h. After cooling, the reaction mixture was diluted with water and the aqueous layer was decanted and rejected. The residue was shaken with CH 2 C1 2 and aqueous Na 2 C0 3 . The organic phase was washed with water, dried over Na 2 S0 4 and evaporated in vacuum to give a white solid.
  • N,N' -Bis (4-quinolinyl) -N,N' -dibenzylpentane-1, 5-diamine (Intermediate X) (0.6 g, 1.1 mmol) was dissolved in 2- butanone (100 ml) and 1, 5-diiodopentane (0.50 g, 1.5 mmol) added. The mixture was heated at reflux for 48 h. After removing half of the solvent, the mixture was heated at reflux for a further 24 h. It was cooled, the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 110'C.
  • N,N' -Bis (4-quinolinyl)pentane-1, 5-diamine (starting material F) (0.43 g, 1.0 mmol) was dissolved in a mixture of 2-butanone (50 ml) and dimethyl formamide (10 ml) and a, cn ' -dibromo-p-xylene (0.4 g, 1.5 mmol) added. The mixture was heated at reflux for 3 days. It was cooled, the resulting precipitate was collected by filtration and purified by preparative HPLC to give a white solid, mp: 220 * C (dec) .
  • N,N' -Bis (4-quinolinyl) -but-2-yne-l,4-diamine (0.28 g, 0.83 mmol) was dissolved in a mixture of 2-butanone (50 ml) and dimethyl formamide (10 ml) with heating and 1, 5-diiodopentane (0.28 g, 0.86 mmol) added. The mixture was heated at reflux for 5 days. After cooling, the precipitate produced was collected by filtration and purified by preparative HPLC to give a white solid, mp: 226"C dec.
  • 1,5(1,4) -dipyridinacyclodecaphanium dibromide 1,5(1,4) -dipyridinacyclodecaphanium dibromide.
  • 1,1' - (m-xylylene) -N 4 , N 4 '-(p- xylylene) -bis(3,4-diaminopyridinium) dibromide N,N' -Bis (3-aminopyridin-4-yl) -xylene- ⁇ , a' -diamine (0.12 g, 0.38 mmol) and a, a' -dibromo-m-xylene (0.10 g, 0.38 mmol) was dissolved with heating in pentan-1-ol (65 ml) .
  • N,N' -Bis (3-aminopyridin-4-yl) -xylene- ⁇ , a' -diamine (0.15 g, 0,47 mmol) and 1, 5-diiodopentane (0.15 g, 0.47 mmol) was dissolved with heating in pentan-1-ol (60 ml) .
  • the solution was heated at reflux for 6 days with stirring. During the course of the reaction a brown precipitate was formed. After cooling, the solid was collected by vacuum filtration. The brown solid was washed with methanol and dried in vacuuo (100 * C) to yield a beige solid, mp: 290'C.
  • apamin acts at the same K + channel and in the same way as the compounds of the present invention, reduces spontaneous and evoked electrical activity in the muscle of patients with myotonic muscular dystrophy [Behrens, M I., Jalil, P., Serani, A., Vergara, F. and Alvarez, 0. (1994) . Possible role of apamin-sensitive K + channels on myotonic dystrophy. Muscle & nerve, 17: 1264 - 1270] . However, apamin' s central neurotoxicity rules out its systemic use; the compounds of the present invention are likely to be more selective in their action in reducing the hyperexcitability associated with this condition.
  • the inventors have found that compounds of the present invention, by blocking SK Ca channels, increase the amplitude of peristalsis in intestinal smooth muscle at unprecedently low concentrations for a low molecular weight synthetic compound.
  • the EC 50 values for Compound 24 and Compound 10 are 0.5 nM and 1 nM respectively, as tested on isolated rabbit jejunum. This shows that the compounds of the present invention may act as a novel prokinetic agent for the treatment of gastrointestinal dysmotilities.
  • the parenteral administration of very small doses of apamin has been shown to facilitate memory processes involved in task learning in mice [Messier, c, Mourre, C, Bontempi, B., Sif, J. , Lazdunski. M. and Destrade, C. (1991) .
  • apamin a toxin that inhibits Ca 2+ - dependent K + channels, on learning and memory processes.
  • Post-test apamin injection suppresses a Kamin-like effect following a learning session in mice. Neuroreport . 6: 1293-1296] .
  • the compounds of the present invention are likely to exert the same action as apamin in the treatment of disorders of memory, but with greater selectivity.
  • Narcolepsy and associated disorders are associated with the premature onset of rapid-eye-movement (REM) sleep.
  • Intraventricularly-administered apamin produces a dose- dependent reduction in REM sleep expression in rats [Benington, J. , Woudenberg, M.C. and Heller, H.C. (1995) .
  • Apamin a selective SK channel blocker, suppresses REM sleep without a compensatory rebound. Brain Research, 692: 86 - 92] .
  • the compounds of the present invention are likely to exert the same action as apamin, but with greater selectivity.
  • dequalinium and other lipophilic cationic compounds are likely to have anticarcinoma activity [Weiss et . al . , Proc. Natl. Acad. Sci. USA. 1987, 8 ⁇ , 5444-8. Gamboa-Vujicic et. al, J. Pharm. Sci. 1993, 82, 231. Helige et . al, Eur. J. Cancer, 1993, 29A, 124.]
  • the compounds of the present invention are likely to exert similar action, but with greater selectivity.
  • Dequalinium is commonly found as an antibacterial agent, particularly in throat lozenges and similar preparations. It is therefore expected that the compounds of the present invention would exhibit antibacterial properties and could be used in medicaments, e.g. throat lozenges, swabs, as such.
  • the compounds of the present invention will exhibit selectivity between different types of SK Ca channels. This may be due to some feature of the structure of the compounds of the present invention conferring the ability to discriminate between the different types of channel.

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Abstract

A series of compounds for blocking calcium activated potassium channels in rat sympathetic neurones and other mammalian cells, and a method for producing them. These compounds with general formulae (I) and (II), where A and B are spacing groups of 3 to 15 carbon atoms Q- is the conjugate base of an acid, R?1 and R4¿ are for example (a), R?2 and R3¿ are for example H, and X is for example NH, exhibit a high potency and are expected to show selectivity between different channel types. The compounds may be useful in the treatment of a number of disorders that are associated with the activity of calcium activated potassium channels, e.g. myotonic muscular dystrophy, gastrointestinal dysmotilities, memory disorders, cancers, narcolepsy and ethanol-induced narcosis. The compounds may also be useful as antibacterial agents.

Description

POTASSIUM CHANNEL BLOCKERS
TECHNICAL FIELD
The present invention relates to compounds having pharmaceutical (including veterinary) use, in particular compounds capable of blocking calcium activated potassium channels in human and other mammalian cells, to methods of making such compounds and to the use of such compounds in the treatment of various disorders.
BACKGROUND OF THE INVENTION
Ca2+-activated K+ channels are found in a wide variety of cell types and can be divided into three main classes on the basis of single channel conductance and sensitivity to blocking agents. Of these, the SKCa channel is characterized by its small single channel conductance (6-20 pS) and high sensitivity to the bee venom toxin apamin. Estimates of the apamin concentration required to cause 50% block of SKCa channels vary considerably between cells, ranging from 0.2 to 20 nM. Also, the action of apamin may reverse rapidly or very slowly, depending on the cell type. From these observations it might be inferred that subtypes of SKCa channels exist .
In recent work by a group including some of the present inventors [British Journal of Pharmacology (1996) 117, 35-42] it has been found that a bis-quaternary quinolinium compound, 8,19-diaza-3, 5 (1,4) -dibenzena- 1, 7 (1,4) -diquinolina-cyclononadecaphane referred to below as Compound A, exhibits the ability to block the SKCa channel in rat sympathetic neurones and guinea-pig hepatocytes. This compound was compared with gallamine and dequalinium; a . large difference in the relative potency of these compounds was found between the two tissues providing strong functional evidence for SKCa channel heterogeneity.
DISCLOSURE OF THE INVENTION
An aim of the present invention is to provide compounds suitable for blocking SKCa channels that are not peptides and are more potent than known compounds.
A further aim of the present invention is to provide compounds that exhibit selectivity in blocking SKCa channels in different cells.
A first aspect of the present invention provides a compound having the general formula I or II:
Figure imgf000005_0001
or any one of its conjugate bases where : each Q" is the conjugate base of a pharmaceutically acceptable inorganic or organic acid;
Ri is selected from H and
Figure imgf000005_0002
R5 being selected from H, and substituents such as a halogen, an alkyl group with 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group;
R2 and R3 are independently selected from H, and substituents such as a halogen, an alkyl group with 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group; R4 is selected from H and Rc
Figure imgf000006_0001
R6 being selected from H, and substituents such as a halogen, an alkyl group with 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group; where R2, R3, R5 and R6 may be present once or a plural number of times on the respective rings; each X is independently selected from NH, NR7, O, S and CH2, R7 being selected from alkyl, aryl, alkaryl and aralkyl groups having 1 to 10 carbon atoms; A and B which are the same or different, are each selected from a spacing group with a chain length of 3 to 15 atoms; except that in general formula I when
Figure imgf000006_0002
R2 and R3 are H, X is NH, and A is (CH2)10,
B cannot be
Figure imgf000006_0003
The term "chain length" throughout this description and claims should be taken to mean the lowest number of atoms between one end of the spacing group and another. The spacing group may contain rings, e.g. cycloalkyl and aromatic, including heterocyclic, substituted or unsubstituted. The spacing groups may contain one or more O or S atoms as part of the chains. The type of linkages possible with these atoms are for example an ether linkage (-0-) ,and thio linkages (-S-) and (-S-S-) . To avoid instability these linkages should not be adjacent to the N atoms of the pyridine or quinoline rings or to X if X is NH, O or S. Aditionally it is preferable that no methylene group has a hetero atom on both sides.
Examples of the spacing groups A and B are given below. The preferred chain length is 3 to 10, more preferably 4 to 7.
It is preferred that X is NH, R1 and R4 are
-£?\ and R2 and R3 are H.
When any of R2,R3,R5 and R6 are not H, it may be any substituent which is pharmaceutically acceptable and which does not remove the potency of the molecule in the effects described herein, in particular the blocking of Ca2+-activated K+ channels. Some suitable substituents are given above. Others are such as acyl, -CH, etc. Compounds which have shown greater potency for blocking SKCa channels are where A is selected from -(CH2)n-, where n=3-6,
Figure imgf000008_0001
and
Figure imgf000008_0002
and B is selected from -(CH2)n- where n=4-6,
Figure imgf000008_0003
and
Figure imgf000008_0004
R7 is selected from H, OH, OMe.
The two most potent compounds are where both A and B are -(CH2)5- and where A is
and B is
Figure imgf000008_0006
These spacing groups have a chain length of 5 and 6 respectively.
Without being bound by theory, it can be supposed that the compounds of the present invention work as potassium channel blockers by the virtue that they exhibit the property of a relatively determined spatial relationship between the two pyridine or quinoline rings of the compound; the two spacing groups hold the two pyridine or quinoline rings in this spatial relationship. This relationship may not be obtained when only one spacing group is present between the two pyridine or quinoline rings since the conformation of the spacing group changes. It appears to the present inventors that the chain length between the two pyridine or quinoline rings affects the potency of the compound as a SKca channel blocker. For these reasons, it is at present believed that the function of the spacing groups is primarily to provide a stable linkage between the two pyridine or quinoline rings, the chemical nature of these spacing groups being preferably relatively inert.
In the compounds of the invention, the substituent groups such as alkyl, alkylamono, alkoxy, aryl, aralkyl and alkaryl mentioned above may be optionally substituted by substituents which do not remove the desired effect of the compound. A second aspect of the present invention provides a method for producing a compound of the invention as described above having the general formula I, by reacting a compound of the general formula:
Figure imgf000010_0001
wiith a compound of the formula H:2N - A - NH to give
Figure imgf000010_0002
which is then further reacted with a compound of the formula Z - B - Z to give
Figure imgf000010_0003
or any one of its conjugate bases, where Y and Z are independently selected from a sulphonate,
CI, Br and I. There is further provided a method for producing a compound of the invention as described above having the general formula I, by reacting a compound of the general formula
Figure imgf000011_0001
with a compound of the general formula
Z - B - Z to give
Figure imgf000011_0002
where Z is selected from Cl, Br and I.
In yet another aspect of the invention there is provided a method for producing a compound of the invention as described above having the general formula II, by reacting a compound of the general formula III
Figure imgf000012_0001
with a compound of the general formula IV
Figure imgf000012_0002
to give
Figure imgf000012_0003
where Y and Z are independently selected from CI, Br and I.
In this method Compounds III and IV may be identical.
Pharmaceutically acceptable acids as mentioned in the above two aspects are exemplified by hydrochloric, hydrobromic, boric, phosphoric, sulphuric, acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, trifluoroacetic and glucose-1-phosphoric acids. A third aspect of the present invention provides the use of compounds of the present invention in the treatment of any one of the following disorders: myotonic muscular dystrophy, gastrointestinal dysmotilities, disorders of memory, narcolepsy and associated disorders, cancers, ethanol-induced neurotoxicity and bacterial infection.
A fourth aspect of the present invention provides the use of compounds of the present invention in the preparation of a pharmaceutical for the treatment of any one of the following disorders: myotonic muscular dystrophy, gastrointestinal dysmotilities, disorders of memory, narcolepsy and associated disorders, cancers, ethanol-induced neurotoxicity and bacterial infection.
A fifth aspect of the present invention provides a pharmaceutical composition containing a compound of the present invention.
In accordance with the present invention, compositions provided may be administered to human individuals or used as a veterinary medicine, particularly for other mammals. Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and time- course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, eg decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors.
Pharmaceutical compositions according to the present invention, and for use in accordance with the present invention, may comprise, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous or intravenous.
Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, tonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
EXAMPLES
Embodiments of the invention will now be given in detail by way of example. We describe syntheses of compounds of the invention, identified as Compound 1 etc., and of intermediates and starting materials.
In the following syntheses of compounds 1 to 41, where preparative high performance liquid chromatography (HPLC) was performed, it was carried out with a Gilson apparatus using a UV detector and a Kromasil C18 5 μm column. Solvent mixtures of water + 0.1% trifluoroacetic acid (TFA) and MeOH + 0.1% TFA were used with a flow rate of 20 ml/min. In many cases, some excess TFA is retained in the salts after HPLC, as well as CH3OH and H20.
mp is melting point, but where this is followed, by (dec) or (decomp) , it indicates decomposition at the temperature given. bp is boiling point.
MeOH is CH3OH, EtOH is C2H5OH, DMF is dimethyl formamide.
The structures of the Compounds 1 to 41 of the invention can all be represented by the general formula:
Figure imgf000016_0001
An alternative structural representation is
Figure imgf000017_0001
which illustrates the conjugate base.
Groups A and B are detailed in Table 1 for each of Compounds 1 to 41.
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Intermediate I 1, 10-Di (quinoline-4-yl)aminodecane:
4-chloroquinoline (2 g, 12.2 mmol) and 1,10- diaminodecane (1.054 g, 6.12 mmol) were dissolved with heating in 1-pentanol (40 ml) and heated under reflux for 30 h. On cooling a creamy precipitate formed which was collected, dissolved in MeOH, made alkaline with 10% aqueous NaOH, diluted with water and left overnight. The product was collected, and crystallised (MeOH) and had mp: 169-171*C. Analysis for C28H34N4, 0.3 CH3OH, 0.2 H20. Calculated:C, 77.28, H, 8.16; N, 12.74%. Found: C, 76.91; H, 7.77; N, 12.77%
Compound 1 7,18-Diaza-3,4 (1,4) -dibenzena-1,6 (1,4) - diquinolinacyclooctadecaphane tri-trifluoroacetate hydrate. Alternatively named: 1,1'- (p,p ' ~ dimethylenebiphenyl) -N4, N4' , decamethylene-bis- (4- aminoquinolinium) tri-trifluoroacetate hydrate: 1, 10-di (quinolin-4-yl) aminodecane (0.2 g, 0.469 mmol) (Intermediate I) and 4,4'- bis (bromomethyl)biphenyl (0.160 g, 0.470 mmol) were dissolved with heating in 2-butanone (50 ml) and then heated, with stirring, under reflux for 72 h. The product was collected by filtration and purified by preparative HPLC, then dissolved in the minimum amount of cold 2-propanol, filtered by gravity and the solvent removed in vacuo. This yielded an off white solid, mp: 280-282 °C.
Analysis for C42H44N4, 3.4 CF3COOH, 1.4 H20. Calculated:C, 57.59, H, 4.97; N, 5.5%. Found: C, 57.81; H, 5.31; N, 5.71%.
Compound 2
7,18-Diaza-3,4(1,3) -dibenzena-1,6 (1,4) - diquinolinacyclooctadecaphane tetra-trifluoroacetate dihydrate. Alternatively named: l,l'-(m,m'- dimethylenebiphenyl) - N4, N4'-decamethylene-bis- (4- aminoquinolinium) tetra-trifluoroacetate dihydrate: 1, 10-di (quinolin-4-yl) aminodecane (0.120 g, 0.281 mmol) (Intermediate I) and 4, 4 ' -bis (bromomethyl)biphenyl (0.096 g, 0.281 mmol) were dissolved with heating in 2- butanone (30 ml) and then heated, with stirring, under reflux for 39 h. The product was collected and purified as described above to yield an off-white solid, mp: 112-114 °C. Analysis for C42H44N4, 4.2
CF3COOH, 2.2 H20. Calculated: C, 53.89, H, 4.72; N, 4.99%. Found: C, 53.81; H, 4.94; N, 5.09%.
Compound 3 6,17-Diaza-3 (2,7) -fluorena-1,5 (1,4) - diquinolinacycloheptadecaphane tetra-trifluoroacetate dihydrate. Alternatively named: 1,1'- (2,7- dimetbylenefluorene) - N4, N4'-decamethylene-bis- (4- aminoquinolinium) tetra-trifluoroacetate dihydrate:
1, 10-di (quinolin-4-yl) aminodecane (0.147 g, 0.344 mmol) (Intermediate I) and 2, 7-di (bromomethyl) fluorene
(0.120 g, 0.343 mmol) were dissolved with heating in 2- butanone (35 ml) and then heated, with stirring, under reflux for 39 h. The product was collected and purified as above to yield an off-white solid, mp: 214- 216 °C. Analysis for C43H44N4, 3.9 CF3COOH, 2 H20.
Calculated: C, 55.59, H, 4.77; N, 5.10%. Found: C, 55.57; H, 5.02; N, 5.03%.
Compound 4 9,20-Diaza-3, 6 (1,4) -dibenzena-1, 8 (1,4) - diquinolinacycloicosaphane tri-trifluoroacetate hydrate. Alternatively named: 1,1'- (p,p'- dimethylenebibenzyl) -N4,N4'-decamethylene-bis- (4- aminoquinolinium) tri-trifluoroacetate hydrate: 1, 10-di (quinolin-4-yl) aminodecane (0.200 g, 0.469 mmol) (Intermediate I) and bis (p-bromomethyl)bibenzyl (0.173 g, 0.470 mmol) were dissolved with heating in 2- butanone (50 ml) and heated, with stirring, under reflux for 36 h. The product was purified as above to yield an off-white solid, mp: 202-204 °C. Analysis for C43H46N4, 3.2 CF3COOH, 1.2 H20. Calculated: C, 59.38, H, 5.3; N, 5.5%. Found: C, 59.25; H, 5.38; N, 5.76%.
Compound 5
9,20-Diaza-3,6 (1,4) -dibenzena-1,8 (1,4) -diquinolina-4- (Z) -enecycloicosaphane tetra-trifluoroacetate dihydrate. Alternatively named: 1,1'- (p,pf- dimethylene- (Z) -stilbene) -N4,^4'-decamethylene-bis- (4- aminoquinolinium) tetra-trifluoroacetate dihydrate: 1, 10-di (quinolin-4-yl) aminodecane (0.200 g, 0.469 mmol) (Intermediate I) and 4,4 ' -bis (bromomethyl) - (Z) - stilbene (0.172 g, 0.469 mmol) were dissolved with heating in 2-butanone (50 ml) and heated, with stirring, under reflux for 46 h. The product was collected and purified as described above to yield an off-white solid, mp: 184-186 °C. Analysis for C44H46N4, 4.2 CF3COOH, 2.2 H20. Calculated: C, 54.76, H, 4.79; N, 4.87%. Found: C, 54.85; H, 5.12; N, 4.88%.
Intermediate II 4,4' -Di- (quinolin-4-yl)aminomethylbiphenyl:
4-Chloroquinoline (1.6 g, 9.6 mmol) and 4,4'- di (aminomethyl)biphenyl (1.0 g, 4.8 mmol) were dissolved with heating in 1-pentanol (32 ml) and heated under reflux for 48 h. On cooling a creamy precipitate formed which was collected, dissolved in MeOH (350 ml) , made alkaline with 10% aq NaOH diluted with water and left overnight . The product formed was collected and crystallized from MeOH-CHCl3-petroleum ether (bp 40-60 °C) and dried to give 1.5 g; mp: 250- 252 °C dec. Analysis for C32H2eN4, 0.8 CH30H. Calculated: C,
80.04, H, 5.98; N, 11.38%. Found: C, 80.12; H, 6.15; N, 11.28%.
Compound 6 13,18-Diaza-15,16(l,4) -dibenzena-1,12 (1,4) - diquinolinacyclooctadecaphane tri-trifluoracetate hydrate. Alternatively named: 1,1' -decamethylene- N4,!!4'- (p,p'-dimethylenebiphenyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate hydrate: 4,4 ' -Di- (quinolin-4-yl)aminomethylbiphenyl (0.1 g, 0.214 mmol) (Intermediate II) and 1, 10-diiododecane (0.09 g, 0.214 mmol) were dissolved with heating in 2-butanone (50 ml) and heated, with stirring, under reflux for 120 h. The product was collected by filtration (0.140 g) and then purified by preparative HPLC. The isolated product was dissolved in the minimum amount of cold 2- propanol, filtered by gravity and the solvent removed in vacuo . This yielded a yellow solid, mp: 233-234 °C dec. Analysis for C42H44N4, 3.1 CF3C00H, 1.1 H20. Calculated: C, 59.19, H, 5.08; N, 5.73%. Found: C, 59.03; H, 5.14; N, 5.72%. Compound 7
7,12-Diaza-3,4,9,10 (1,4) -tetrabenzena-1, 6 (1,4) - diquinolinacyclododecaphane hexa-trifluoroacetate tetrahydrate. Alternatively named: 1,1' -(p,p'~
Dimethylenebiphenyl) -N4,N4'- (p,p '-dimethylenebiphenyl) - bis- (4-aminoquinolinium) hexa-trifluoroacetate tetrahydrate: 4,4 ' -Di- (quinolin-4-yl) aminomethylbiphenyl (0.25 g, 0.536 mmol) (Intermediate II) and 4,4'- di (bromomethyl)biphenyl (0.18 g, 0.53 mmol) were dissolved with heating in 2-butanone (50 ml) and heated, with stirring, under reflux for 60 h. The product was collected by filtration (0.40 g) and then purified by preparative HPLC. The isolated product was dissolved in the minimum amount of cold 2-propanol, filtered by gravity and the solvent removed in vacuo to yield a solid, mp: 140-142 °C. Analysis for C46H36N4, 6 CF3COOH, 4 H20. Calculated: C, 49.72, H, 3.60; N, 4.00%. Found: C, 49.47; H, 3.91; N, 3.95%.
Intermediate III
27i-Bis [ (quinolin-4-yl)aminomethyl]benzene hydrate:
4-Chloroquinoline (0.800 g, 0.489 mmol) and m- di (aminomethyl)benzene (0.340 g, 2.49 mmol) were dissolved with heating in 1-pentanol (20 ml) and heated under reflux for 41.5 h and then evaporated to afford an oil which crystallized after 2 days. The latter was suspended in MeOH (120 ml) , made alkaline with 10% aqueous NaOH (40 ml) and stirred for 3 h. The product was collected by filtration, dried, and crystallized from MeOH (120 ml) to give beige crystals, mp: 243-246 °C (decomp) . Analysis for C26H22N4, 1.7 H20. Calculated: C, 74.16, H, 6.08; N, 13.3%. Found: C, 74.06; H, 5.79; N, 12.97%.
Compound 8
6,10-Diaza-3,8 (1,3) -dibenzena-1,5 (1,4) - diquinolinacyclodecaphane di-trifluoroacetate dihydrate. Alternatively named: 1,1', N^t^'-bis (m- dimethylenebenzene) -bis(4-aminoquinolinium) di- trifluoroacetate dihydrate: m-Bis [ (quinolin-4-yl) aminomethyl] -benzene (0.210 g, 0.0616 mmol) (Intermediate III) and m-di (bromomethyl) - dibenzene (0.146 g, 0.0553 mmol) were dissolved with heating in 2-butanone (25 ml) and heated, with stirring, under reflux for 23 h. The product was collected by filtration (0.333 g) and purified by preparative HPLC. The resulting product was then dissolved in the minimum amount of cold 2-propanol, filtered by gravity and the solvent removed in vacuo to yield a white microcrystalline compound; mp: 224-226 °C (decomp) . Analysis for C34H28N4, 2 CF3COOH, 2.4 H20. Calculated: C, 59.75, H, 4.59; N, 7.33%. Found:C, 59.77; H, 4.70; N, 7.12.%.
Compound 9
6,10-Diaza-8, (1,3) ,3 (1,4) -dibenzena-1,5 (1,4) - diquinolinacyclodecaphane di-trifluoroacetate hydrate. Alternatively named: [1,1' - (p-dimethylenebenzene) - N4,N4'- (m-dimethylenebenzene) ] -bis(4-aminoquinolinium) di-trifluoroacetate hydrate:
Likewise m-bis [ (quinolin-4-yl) aminomethyl] -benzene (0.210 g, 0.0538 mmol) (Intermediate III) and p- di (bromomethyl) -benzene (0.146 g, 0.0553 mmol) were heated together in 2-butanone (30 ml) for 23 h and the product purified by preparative HPLC to yield a white powder, mp: 234-236 °C (decomp) . Analysis for C34H28N4, 2 CF3C00H, 1.1 H20. Calculated: C, 56.22, H, 3.92; N, 6.56%. Found: C, 55.94, H, 4.00; N, 6.38%.
Intermediate IV p-Bis [ (quinolin-4-yl)aminomethyl]benzene (a starting product) :
4-Chloroquinoline (0.80 g, 4.89 mmol) and p- bis (aminomethyl)benzene (0.34 g, 2.49 mmol) were heated in 1-pentanol (20 ml) under reflux for 41.5 h. In the course of the reaction a creamy precipitate formed which was collected by vacuum filtration. The 1- pentanol filtrate was concentrated to dryness and the resulting oil left to solidify (2 days) . The two products were combined and suspended in MeOH (120 ml) , made alkaline with aqueous NaOH (10%, 40 ml) and stirred for 3 h. The product was filtered off, dried, and recrystallized (MeOH, 120 ml) to give cream crystals (0.573 g, 57.7 %) ; mp: 278-279*C (decomp) . Analysis for C26H22N4, 0.4 H20. Calculated: C, 78.52, H, 5.78; N, 14.09%. Found: C, 78.46; H, 5.90; N, 13.92%.
Compound 10
6,10-Diaza-3 (1,3) ,8 (1,4) -dibenzena-1,5 (1,4) - diquinolinacyclodecaphane tri-trifluoroacetate hydrate. Alternatively named: [1,1'- (m-dimethylene- benzene) - N^N4'- (p-dimethylenebenzene) ] -bis(4-aminoquinolinium) tri-trifluoroacetate hydrate: p-Bis [ (quinolin-4-yl) aminomethyl]benzene (0.180 g, 0.046 mmol) (Intermediate IV) and m-di (bromo¬ methyl)benzene (0.122 g, 0.046 mmol) were dissolved with heating in 2-butanone (25 ml) and heated with stirring under reflux for 23 h. The resulting product was filtered off and purified by preparative HPLC; it was then dissolved in the minimum amount of cold 2- propanol, filtered, and the solvent was removed in vacuo to yield the white crystalline product; mp: 255- 257 °C (decomp) . Analysis for C34H28N4, 3 CF3COOH, H20. Calculated: C, 56.34, H, 3.90; N, 6.57%. Found:C, 56.72, H, 4.21; N, 6.42%.
Compound 11
32-Hydroxy-6,10-diaza-3 (1,3) ,8 (1,4) -dibenzena-1,5 (1,4) - diquinolinacyclodecaphane trihydrobromide methanolate. Alternatively named: [1,1'- (1,3-dimethylene-2- hydroxybenzene) -N4,N4'- (1,4-dimethylenebenzene) ] -bis- (4- aminoquinolinium) dibromide hydrobromide methanolate: A mixture of 2, 6-dimethylanisole (1.8 g, 14 mmol) , N- bromosuccinimide (4.9 g, 30 mmol) and dibenzoyl peroxide (0.4 g, 1.8 mmol) in carbon tetrachloride (50 ml) was stirred and heated under reflux for 4 h, cooled and filtered to remove the solid. The solvent was distilled off to give an oil which solidified on cooling and was crystallised from hexane ethylacetate to give 2, 6-di (bromomethyl) anisole as a pale yellow crystalline solid, mp: 90-91 °C.
To the latter (1.28 g, 4.25 mmol) in dichloromethane (50 ml) was added boron tribromide (0.53 g, 2.15 mmol) as a 1M solution in dichloromethane. The mixture was heated under reflux with stirring for 18 h, cooled and poured onto icewater (100 ml) . The organic layer was separated, dried (MgS04) and evaporated to yield 2,6- di (bromomethyl)phenol, mp: 80-82 °C.
To a refluxing solution of p-bis [ (quinolin-4- yl) aminomethyl] -benzene (0.2 g, 0.051 mmol) (Intermediate IV) in 2-butanone (40 ml) was added 2, 6-di (bromomethyl)phenol (0.17 g, 0.060 mmol) dissolved in 2-butanone (5 ml) and the mixture was heated with stirring under reflux for 42 h. The product was collected by filtration and crystallised from methanol to yield a pale yellow crystalline solid, mp: 280-282 °C decomp. Analysis for C34H28N40, 3 HBr, CH30H. Calculated: C, 53.66, H, 4.50; N, 7.15%. Found: C, 53.56, H, 4.54; N, 6.86%.
Compound 12
32-Hydroxy-35-iodo-6,10-diaza-3 (1,3) ,8 (1,4) -dibenzena- 1,5(1,4) -diquinolinacyclodecaphane dihydroiodide methanolate hemihydrate. Alternatively named: [1,1'- (l,3-dimethylene-2-hydroxy-5-iodobenzene) -N4,!*4'- (1,4- dimethylenebenzene) ] -bis- (4-aminoquinolinium) diiodide methanolate hemihydrate.
To a solution of the above cyclophane Compound 11 (0.01 g, 0.162 mmol) and sodium iodide (0.0029 g, 0.195 mmol) in DMF (0.8 ml) at 28 °C was added chloramine T (0.0055 g, 0.195 mmol) and the mixture was stirred at 28 °C for 1 h, then diluted with water (2 ml) and acidified with 5% HCI. The solid which separated was filtered off, washed with water (2 ml) , then with sodium thiosulphite solution, and dried to afford a solid which, after crystallisation from methanol, yielded the product as a yellow solid, mp: 260 °C decomp. Analysis for C34H27IN40, 2 HI, CH30H, 0.5 H20. Calculated: C, 45.14, H, 3.68; N, 6.01%. Found: C, 45.37, H, 3.62; N, 5.60%.
Compound 13
32-Methoxy-6,10-diaza-3 (1,3) ,8 (1,4) -dibenzena-1,5 (1,4) - diquinolinacyclodecaphane dihydrobromide dihydrate. Alternatively named: [1,1'- (l,3-dimethylene-2- methoxybenzene) -N4,!!4'- (1,4-dimethylenebenzene) ] -bis- (4- aminoquinolinium) dibromide dihydrate. To a refluxing solution of p-bis [ (quinolin-4- yl) aminomethyl] -benzene (0.15 g, 0.038 mmol) (Intermediate IV) in 2-butanone (30 ml) was added 2, 6-di (bromomethyl)anisole (0.14 g, 0.05 mmol) dissolved in 2-butanone (5 ml) and the mixture was heated with stirring under reflux for 42 h. The product was collected by filtration and crystallised from methanol to give an off white solid, mp: 282-285 °C decomp. Analysis for C35H30N4O, 2 HBr, 2 H20.
Calculated: C, 58.35, H, 5.04; N, 7.78%. Found: C, 58.60, H, 4.94; N, 7.55%.
Compound 14
6,10-Diaza-3,8(1,4) -dibenzena-1,7(1,4) - diquinolinacyclodecaphane tri-trifluoroacetate hydrate. Alternatively named: [1,1' jN4,!!4'-bis(p- dimethylenebenzene) ] -bis(4-aminoquinolinium) tri- trifluoroacetate hydrate: p-Bis [ (quinolin-4-yl)aminomethyl]benzene (0.180 g, 0.046 mmol) (Intermediate IV) and p- di (bromomethyl)benzene (0.122 g, 0.046 mmol) were dissolved with heating in 2-butanone (25 ml) and heated with stirring under reflux for 23 h. The resulting product was filtered off and purified by preparative HPLC; it was then dissolved in the minimum amount of cold 2-propanol, filtered, and the solvent was removed in vacuo to yield the white solid product; mp: 326-328 °C (decomp) . Analysis for C34H28N4, 3 CF3C00H, 1.2 H20. Calculated: C, 56.11, H, 3.93; N, 6.54%. Found:C, 56.10, H, 4.19; N, 6.38%.
Intermediate V
4,4' -Bis[ (quinolin-4-yl)aminomethyl]diphenylmethane dimethanolate: 4-Chloroquinoline (1.45 g, 9 mmol) and 4,4'- bis (aminomethyl) diphenylmethane (1 g, 4.42 mmol) were dissolved with heating in 1-pentanol (50 ml) and then heated under reflux for 47 h. The suspension was then concentrated to dryness and the resulting solid (3.26 g) was dissolved in MeOH (100 ml) , made alkaline with aqueous NaOH (10 %, 40 ml) , and stirred for 19 h. The product was filtered off and dried, and purified by column chromatography (MeOH:CHCl3=l :1) to give a yellowish powder; this was dissolved in dry 2-propanol, filtered, and dried; mp: 116-118 °C (decomp) . Analysis for C33H28N4, 2.3 CH30H, 0.1 H20. Calculated: C, 76.24, H, 6.78; N, 10.07%. Found: C, 76.51, H, 6.72; N, 9.72.%.
Compound 15 8,14-Diaza-3,5,10,12 (1,4) -tetrabenzena-1,7(1,4) - diquinolinacyclotetradecaphane tri-trifluoroacetate dihydrate. Alternatively named: 1,1' jN4,!!4'- [p,p' - dimethylenediphenylmethane-bis(4-amino-quinolinium) ] tri-trifluoroacetate dihydrate: 4,4 '-Bis [ (quinolin-4-yl)aminomethyl] -diphenylmethane (0.271 g, 0.0564 mmol) (Intermediate V) and 4,4'- bis (bromomethyl)diphenylmethane (0.200 g, 0.0565 mmol) were dissolved with heating in 2-propanone (50 ml) and heated with stirring under reflux for 45 h. The product was collected by filtration and purified by preparative HPLC; it was then dissolved in the minimum amount of cold 2-propanol, filtered, and the solvent removed in vacuo . This yielded an off-white microcrystalline compound; mp: 218-220 °C (decomp) . Analysis for C48H40N4, 3 CF3C00H, 2.2 H20. Calculated: C, 61.50, H, 4.53; N, 5.31%. Found: C, 61.32, H, 4.59; N, 5.24%.
In a similar manner, the following compounds were synthesised:
Compound 16
7,13-Diaza-3,4,9,11(1,4) -tetrabenzena-1,6 (1,4) - diquinolinacyclotridecaphane tetra-trifluoroacetate dihydrate. Alternatively named: [1,1'- (p,p'- dimethylenebiphenyl) -N4,N4'- (p,p' -dimethylene- diphenylmethane) ] -bis (4-aminoquinolinium) tetra- trifluoroacetate dihydrate: From 4,4' -bis [ (quinolin-4-yl)aminomethyl] - diphenylmethane (0.283 g, 0.0588 mmol) (Intermediate V) and 4, 4 ' -bis (bromo-methyl)biphenyl (0.200 g, 0.0588 mmol) to yield a white microcrystalline compound; mp: 224-226 °C (decomp) . Analysis for C48H40N4, 4 CF3COOH, 2 H20. Calculated: C, 57.4, H, 4.03; N, 4.87%. Found: C, 57.72, H, 4.36; N, 4.69%.
Compound 17 9,15-Diaza-3,6,11,13 (1,4) -tetrabenzena-1, 8 (1,4) - diquinolina-4- (Z) -ene-cyclopentadecaphane di- trifluoroacetate trihydrate. Alternatively named: [1,1'- (p,p'-dimethylene- (Z) -stilbene) -N4,*!4'- (p,p' - dimethylenediphenylmethane) ] -bis (4-aminoquinolinium) di-trifluoroacetate trihydrate: From 4,4 ' -bis [ (quinolin-4- yl) aminomethyl]diphenylmethane (0.263 g, 0.0547 mmol) (Intermediate V) and 4,4 ' -bis (bromomethyl) - (Z) - stilbene (0.200 g, 0.0546 mmol) to give the product which was recrystallised from absolute ethanol after the addition of a few drops of diethyl ether to yield a white powder; mp: 267-269 °C (decomp) . Analysis for C48H40N4, 2 CF3COOH, 3.4 H20. Calculated: C, 65.21, H, 5.25; N, 5.74%. Found: C, 65.43, H, 5.17; N, 5.75%.
Compound 18
8,14-Diaza-3,5,10,12 (1,4) -tetrabenzena-4 (2,6) -pyridina-
1,7(1,4) -diquinolinacyclotetradecaphane tri- trifluoroacetate trihydrate dimethanolate. Alternatively named: 1, 1'-{ [2,6-bis (4'- methylenephenyl)pyridine] -N4,N4'" (p,p' - dimethylenediphenylmethane) }-bis(4-aminoquinolinium) tri-trifluoroacetate trihydrate dimethanolate: 4,4 ' -bis [ (quinolin-4-yl) aminomethyl] diphenylmethane
(0.200 g, 0.0416 mmol) (Intermediate V) and 2,6-bis[4'- (bromomethyl) phenyl] pyridine were dissolved with heating in 2-propanone (30 ml) . The solution was heated with stirring under reflux for 40 h and the product collected by filtration. This was treated with boiling EtOH (75 ml) and the insoluble material was filtered off and purified by preparative HPLC. The isolated product was then dissolved in the minimum amount of cold 2-propanol, filtered by gravity and the solvent removed in vacuo to yield an off-white solid; mp: 224-226 °C. Analysis for C52H40N5, 3 CF3COOH, 2 CH3OH, 2.8 H20. Calculated: C, 60.48, H, 4.79; N, 5.88%.Found: C, 60.49, H, 4.89; N, 5.53%.
Intermediate VI 4,4' -Bis [ (quinolin-4-yl)aminomethyl]biphenyl hydrate (a starting product) :
In a similar manner to Intermediate V 4-chloroquinoline (0.231 g, 1.41 mmol) and 4,4 ' -bis (aminomethyl)biphenyl (0.150 g, 0.707 mmol) were heated together in 1- pentanol, and the suspension stirred under reflux for 47 h. The product, after being recrystallized [MeOH, CHC13, petroleum ether (bp: 60-80 °C) ] was obtained as cream crystals; mp: 250-252 °C (decomp) . Analysis for C26H22N4, 1.6 H20. Calculated: C, 77.58, H, 5.94; N, 11.31%. Found:C, 77.54, H, 5.67; N, 11.02% Compound 19
7,13-Diaza-3,4,9,11(1,4) -tetrabenzena-1, 6 (1,4) - diquinolinacyclotridecaphane tetra-trifluoroacetate heptahydrate. Alternatively named: [1,1' -(p,p'~ dimethylenebiphenyl) -N4,N4'- (p, p ' - dimethylenediphenylmethane) ] -bis(4-aminoquinolinium) tetra-trifluoroacetate heptahydrate: From 4,4' -bis [ (quinolin-4-yl) aminomethyl] biphenyl (0.173 g, 0.0371 mmol) (Intermediate VI) and 4,4'- bis (bromomethyl)diphenylmethane (0.131 g, 0.0370 mmol) . The isolated product was obtained as an off-white solid; mp: > 350 °C. Analysis for C48H40N4, 4.5 CF3C00H, 7 H20. Calculated: C, 51.82, H, 4.39; N, 4.32%. Found: C, 52.05, H, 4.62; N, 4.16.%.
Compound 20
6,ll-Diaza-8,9 (1,4) -dibenzena-3 (2,7) -fluorena-1,5 (1,4) - diquinolinacycloundecaphane tetra-trifluoroacetate hexahydrate. Alternatively named: [1,1'- (2,7- dimethylenefluorene) -N4,N4'- (p,p' -dimethylenebiphenyl) ] bis (4-aminoquinolinium) tetra-trifluoroacetate hexahydrate:
From 4,4' -bis [ (quinolin-4-yl) aminomethyl] biphenyl (0.200 g, 0.0429 mmol) (Intermediate VI) and 2,7- bis (bromomethyl) fluorene (0.154 g, 0.0429 mmol) with heating in 2-propanone (50 ml) under reflux for 39 h. After filtration, the collected product was treated with a boiling mixture of EtOH/MeOH (150 ml/50 ml) and the insoluble sample was filtered and purified by preparative HPLC to yield an off-white solid; mp: 316- 319 °C. Analysis for C47H36N4, 4 CF3COOH, 6.6 H20.
Calculated: C, 53.63, H, 4.35; N, 4.55%. Found: C, 53.63, H, 4.58; N, 4.41%.
Compound 21 ll,20-Diaza-l,10 (1,4) -diquinolinacycloicosaphane dihydroiodide sesquihydrate. Alternatively named: 1,1'- (Octane-1, 8-diyl) -N4,!*4'- (octane-1, 8-diyl) -bis- (4- aminoquinolinium) diiodide sesquihydrate. A mixture of 4-chloroquinoline (0.5 g, 3.056 mmol) and 1, 8-diaminooctane (0.220 g, 1.528 mmol) in 1-pentanol (10 ml) was heated under reflux with stirring for 48 h and then cooled. The resulting precipitate was collected, washed with 1-pentanol and diethyl ether, then dissolved in 12 ml of hot methanol, and basified with 3.5 ml of 1M NaOH solution. Water (30 ml) was added into the flask and it was cooled for 1 h. The precipitate was collected, washed extensively with water, and then dried under vacuum at 40 °C for 12 h to give N4, N4'- (octane-1, 8-diyl) -bis- (4-aminoquinoline) as a white crystalline solid (0.6 g, 98% yield) ; mp: 185- 189 °C. A mixture of N4, N4'- (octane-1, 8-diyl) -bis- (4- aminoquinoline) (0.4 g, 1.004 mmol) and 1,8- diiodooctane (0.367 g, 1.004 mmol) in 2-butanone (330 ml) was heated under reflux with stirring for 7 days and then cooled. The resulting precipitate was collected, washed extensively with diethyl ether, dried under vacuum at 40 °C for 12 h to give the product as a yellowish crystalline solid; mp: 248-253 °C. Analysis for C34H46N4I2, 1.5 H20. Calculated: C, 51.57, H, 6.24; N, 7.08%. Found: C, 51.68, H, 5.99; N, 6.78%.
Compound 22
13,24-Diaza-l,12 (1,4) -diquinolinacyclotetraicosaphane tri-trifluoroacetate. Alternatively named: 1,1'- (Decane-1, 10-diyl) -N4, N4'- (decane-1,10-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate.
A mixture of N4, N4'- (decane-1, 10-diyl) -bis- (4- aminoquinoline) prepared in the same way as the intermediate in the synthesis of Compound 21 (0.4 g, 0.9 mmol) and 1,10-diiododecane (0.37 g, 0.9 mmol) in 2-propanone (330 ml) was heated under reflux with stirring for 7 days, then cooled. The resulting precipitate was collected, washed extensively with diethyl ether, and purified by preparative HPLC to give a white crystalline solid; mp: 122-125 °C. Analysis for C38H52N4, 3 CF3C00H. Calculated: C, 58.25, H, 6.12; N, 6.18%. Found: C, 58.53, H, 6.12; N, 6.14%. Compound 23
9, 16-Diaza-l,8(1,4) -diquinolinacyclohexadecaphane tetra-trifluoroacetate. Alternatively named: 1,1'- (Hexane-1,6-diyl) -N4, N4'- (hexane-1, 6-diyl) -bis- (4- aminoquinolinium) tetra- trifluoroacetate.
A mixture of 4-chloroquinoline (0.5 g, 3.05 mmol) and hexamethylenediamine (0.177 g, 1.52 mmol) in 1-pentanol (10 ml) was heated under reflux with stirring for 48 hours and then cooled. The resulting precipitate was collected, washed with 1-pentanol and diethyl ether and then treated as described above in the synthesis of Compound 21 to give N4, N4'- (hexane-1, 6-diyl) -bis- (4- aminoquinoline) as a white crystalline solid (0.55 g, 97% yield) ; mp: 226-230 °C.
A mixture of N4, N4'- (hexane-1, 6-diyl) -bis- (4- aminoquinoline) (0.4 g, 1.080 mmol) and 1,6- diiodohexane (0.365 g, 1.080 mmol) in 2-butanone (330 ml) was heated under reflux with stirring for 7 days and then cooled. The precipitate was collected by filtration, washed extensively with diethyl ether, and purified by preparative HPLC, to give the product as a white crystalline solid; mp: 132-136 °C. Analysis for C30H36N4, 4 CF3C00H. Calculated: C, 50.21, H, 4.44; N, 6.17%. Found: C, 50.10, H, 4.43; N, 6.03%. Compound 24
8,14-Diaza-l,7(1,4) -diquinolinacyclotetradecaphane tetra-trifluoroacetate. Alternatively named: 1,1'- (Pentane-1,5-diyl) -N4, N4'- (pentane-1,5-diyl) -bis- (4- aminoquinolinium) tetra-trifluoroacetate.
A mixture of 4-chloroquinoline (0.5 g, 3.056 mmol) and 1, 5-diaminopentane (0.156 g, 1.528 mmol) in 1-pentanol (10 ml) was heated under reflux with stirring for 48 hours and then cooled. Ether (20 ml) was added and the resulting precipitate was collected, washed with 1- pentanol and diethyl ether and then treated as described above in the synthesis of Compound 21 to give N4, N4'- (pentane-1, 5-diyl) -bis- (4-aminoquinoline) as a white crystalline solid, mp: 204-208 °C. A mixture of N4, N4'- (pentane-1, 5-diyl) -bis- (4-aminoquinoline) (0.475 g, 1.334 mmol) and 1, 5-diiodopentane (0.432 g, 1.33 mmol) in 2-butanone (150 ml) was heated under reflux with stirring for 7 days and then cooled. The resulting precipitate was collected, washed extensively with diethyl ether and purified by preparative HPLC to give the product as a white crystalline solid; mp: 126-130 °C. Analysis for C28H32N4, 4.2 CF3COOH. Calculated: C, 48.37, H, 4.04; N, 6.20%. Found: C, 48.46, H, 3.99; N, 6.27%. Compound 25
7,13-Diaza-l, 6 (1,4) -diquinolinacyclotridecaphane di- trifluoroacetate. Alternatively named: 1,1' - (Butane- 1,4-diyl) -N4, N4'- (pentane-1,5-diyl) -bis- (4- aminoquinolinium) di-trifluoroacetate:
This was prepared similarly to Compound 24 from N4, N4' - (pentane-1, 5-diyl) -bis- (4-aminoquinoline) (0.50 g, 1.41 mmol) and 1, 4-diiodobutane (0.45 g, 1.45 mmol) in 2- butanone (170 ml) heated under reflux for 6 days. The mixture was cooled and the resulting solid was collected, washed well with ether and purified by preparative HPLC to give the product as a white crystalline solid, mp: 201-203 °C. Analysis for C27H30N4, 2.3 CF3COOH. Calculated: C, 56.41, H, 4.84; N, 8.33%. Found: C, 56.44, H, 4.82; N, 8.36%.
Compound 26
9,15-Diaza-l,8(1,4) -diquinolinacyclopentadecaphane tri- trifluoroacetate. Alternatively named: 1, 1'- (Hexane- 1,6-diyl) -N4, N4'- (pentane-1,5-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate:
This was prepared similarly to Example 24 from N4, N4' - (pentane-1, 5-diyl) -bis- (4-aminoquinoline) (0.355 g, 1.00 mmol) and 1, 6-diiodohexane (0.30 g, 0.99 mmol) in 2-butanone (125 ml) heated under reflux for 6 days. The mixture was cooled and the resulting solid was collected, washed well with ether and purified by preparative HPLC to give the product as a white crystalline solid, mp: 195-198 °C. Analysis for C29H36N4, 3.1 CF3C00H. Calculated: C, 53.38, H, 4.72; N, 7.07%. Found: C, 53.24, H, 4.64; N, 7.17%.
Compound 27
7,12-Diaza-l,6(1,4) -diquinolinacyclododecaphane tetra- trifluoroacetate. Alternatively named: 1,1'- (Butane- 1,4-diyl) -N4, N4'- (butane-l,4-diyl) -bis- (4- aminoquinolinium) tetra-trifluoroacetate: A mixture of 4-chloroquinoline (0.5 g, 3.05 mmol) and 1,4-diaminobutane (0.134 g, 1.52 mmol) in 1-pentanol (10 ml) was heated under reflux with stirring for 48 h and then cooled. Ether (20 ml) was added to the mixture and the resulting precipitate was collected, washed with 1-pentanol and diethyl ether and treated as described above in the synthesis of Compound 21 to give N4, N4' - (butane-l,4-diyl) -bis- (4-aminoquinoline) as a white crystalline solid; mp: 258-264 °C.
A mixture of N4, N4' - (butane-l, 4-diyl) -bis- (4- aminoquinoline) (0.22 g, 0.643 mmol) and 1,4- diiodobutane (0.199 g, 0.643 mmol) in 2-butanone (150 ml) was heated under reflux with stirring for 7 days and then cooled. The resulting precipitate was collected, washed extensively with diethyl ether and purified by preparative HPLC to give the product as a white crystalline solid; mp: 138-140 °C. Analysis for C26H28N4, 4.1 CF3COOH. Calculated: C, 47.52, H, 3.75; N, 6.47%. Found: C, 47.40, H, 3.74; N, 6.43%.
Compound 28
8,13-Diaza-1,7(1,4) -diquinolinacyclotridecaphane tri- trifluoroacetate. Alternatively named: 1,1'- (Pentane- 1,5-diyl) -N4, N4'- (butane-l,4-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate:
This was prepared similarly to Compound 27 from N4, N4'- (butane-l,4-diyl) -bis- (4-aminoquinoline) (0.26 g, 0.75 mmol) and 1, 5-diiodopentane (0.21 g, 0.75 mmol) in 2- butanone (85 ml) heated under reflux for 6 days. The mixture was cooled and the resulting solid was collected, washed well with ether and purified by preparative HPLC to give the product as a white crystalline solid, mp: 224-226 °C. Analysis for C27H30N4, 2.7 CF3COOH. Calculated: C, 54.17, H, 4.59; N, 7.80%. Found: C, 54.32, H, 4.53; N, 7.85%.
Compound 29
8, 12-Diaza-1,7 (1,4) -diquinolinacyclododecaphane tri- trifluoroacetate. Alternatively named: 1, 1- (Pentane- 1,5-diyl) -N4, N4' - (propane-1,3-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate:
A mixture of 4-chloroquinoline and 1, 3-diaminopropane (0.113 g, 1.53 mmol) in 1-pentanol (10 ml) was heated under reflux with stirring for 48 h and then cooled. Ether (20 ml) was added into the mixture and the resultant precipitate was collected, washed with 1- pentanol and diethyl ether and treated as described above in the synthesis of Compound 21 to give N4, N4' - (propane-1, 3-diyl) -bis- (4-aminoquinoline) , as a white crystalline solid; mp: 302-306 °C.
A mixture of N4, N4'- (propane-1, 3-diyl) -bis- (4- aminoquinoline) (0.2 g, 0.609 mmol) and 1,5- diiodopentane (0.197 g, 0.609 mmol) in 2-butanone (68 ml) was heated under reflux with stirring for 7 days and then cooled. The resulting precipitate was washed extensively with diethyl ether and purified by preparative HPLC to give the product as a white crystalline solid; mp: 140-144 °C. Analysis for C26H28N4, 3.2 CF3COOH. Calculated: C, 51.09, H, 4.13; N, 7.36%. Found: C, 51.34, H, 4.10; N, 7.31%.
Compound 30
7,ll-Diaza-1,6 (1,4) -diquinolinacycloundecaphane tri- trifluoroacetate. Alternatively named: 1,1 ' - (Butane- 1,4-diyl) -N4, N4'- (propane-1,3-diyl) -bis- (4- aminoquinoquinolinium) tri-trifluoroacetate:
From N4, N4'- (propane-1, 3-diyl) -bis- (4-aminoquinoline) (0.3 g, 0.914 mmol) and 1, 4-diiodobutane (0.283 g, 0.914 mmol) in 2-butanone (250 ml) heated under reflux with stirring for 11 days. It was obtained as a yellowish crystalline solid; mp: 132-134 °C. Analysis for C25H2GN4, 3.4 CF3COOH. Calculated: C, 49.57, H, 3.85; N, 7.28%. Found: C, 49.61, H, 3.78; N, 7.36%.
Compound 31
6,10-Diaza-1,5 (1,4) -diquinolinacyclodecaphane tri- trifluoroacetate. Alternatively named: 1,1'- (Propane- 1,3-diyl) -N4, N4'- (propane-1,3-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate: This was prepared in a similar manner to Compound 29 from N4, N4' - (propane-1, 3-diyl) -bis- (4-aminoquinoline) (0.2 g, 0.609 mmol) and 1, 3-diiodopropane (0.180 g, 0.609 mmol) in 4-methyl-2-pentanol (58 ml) heated under reflux with stirring for 6 days. It was obtained as a green-yellowish crystalline solid and contained about 7% of Compound 32; mp: 138-140 °C. Analysis for C24H24N4, 3.2 CF3COOH. Calculated: C, 49.62, H, 3.86; N, 7.63%. Found: C, 49.79, H, 3.74; N, 7.64%.
Compound 32
The above reaction procedure was repeated and the initially formed solid product was collected and 0.4 g heated in trifluoroacetic acid (2.5 ml) and MeOH (7.5 ml) under reflux with stirring for 7 days. Preparative HPLC was then used to separate an isomer of the above Compound 31 (cis or trans isomer) . It contained about 12% of Compound 31; mp: 215-217 °C. Analysis for C24H24N4, 3.2 CF3C00H, 0.5 H20. Calculated: C, 49.19, H, 3.83; N, 7.55%. Found: C, 49.47, H, 4.20; N, 7.45%.
Compound 33
8,12-Diaza-10 (1,4) -benzena-1,7(1,4) - diquinolinacyclododecaphane di-trifluoroacetate. Alternatively named: 1,1'- (Pentane-1,5-diyl) -N4, N4'- (p- dimethylenebenzene) -bis- (4-aminoquinolinium) di- trifluoroacetate:
4-Chloroquinoline (3.0 g, 18.3 mmol) and p- di (aminomethyl)benzene (1.25 g, 9.17 mmol) in 1- pentanol (60 ml) were heated under reflux with stirring for 2 days, then cooled. The resulting precipitate was collected, suspended in 300 ml of methanol, basified with 150 ml of 10% NaOH solution and stirred overnight. The solid was filtered off, washed extensively with water, dried at 40 °C under vacuum for 4 h to give N4, N4' - (p-dimethylenebenzene) -bis (4-aminoquinoline) as a pale yellow solid; mp: 278-280 °C(dec) . A mixture of N4, N4' - (p-dimethylenebenzene) -bis- (4- aminoquinoline) (0.5 g, 1.28 mmol) and 1,5- diiodopentane (0.41 g, 1.28 mmol) in 2-butanone (83 ml) was heated under reflux with stirring for 2 days, then cooled. The resulting precipitate was collected, washed extensively with diethyl ether and purified by preparative HPLC to give the product as a white crystalline solid, which was dried in vacuo at 40 °C for 3 days and had mp: 308-310 °C. Analysis for C31H30N4, 2.2 CF3COOH. Calculated: C, 59.93, H, 4.57; N, 7.90%. Found: C, 59.70, H, 4.60; N, 7.80%.
Compound 34 7,11-Diaza-9(1,4) -benzena-1,6 (1,4) - diquinolinacycloundecaphane di-trifluoroacetate sesquihydrate. Alternatively named: 1,1'- (Butane-l,4- diyl) -N4, N4' (p-dimethylenebenzene) -bis- (4- aminoquinoline) ditrifluoroacetate sesquihydrate: This was prepared in a similar manner to Compound 33 from N4, N4'- (p-dimethylenebenzene) -bis- (4- aminoquinolinium) and 1,4-diiodobutane and obtained as a white crystalline solid; mp: 248-250 °C(dec) . Analysis for C30H28N4, 2 CF3COOH, 1.5 H20. Calculated: C, 58.35, H, 4.76; N, 8.01%. Found: C, 58.19, H, 4.91; N, 8.23%. Compound 35
9,13-Diaza-ll (1,4) -benzena-1,8 (1,4) - diquinolinacyclotridecaphane di-trifluoroacetate. Alternatively named: 1,1' - (Hexane-1,6-diyl) -N4, N4'- (p- dimethylenebenzene) -bis- (4-aminoquinolinium) di- trifluoroacetate:
This was similarly prepared from N4, N4'-(p- dimethylenebenzene) -bis- (4-aminoquinolinium) and 1,6- diiodohexane and obtained as a white crystalline solid; mp: 251-253 °C. Analysis for C32H32N4, 2.2 CF3C00H. Calculated: C, 60.43, H, 4.76; N, 7.74%. Found: C, 60.73, H, 5.00; N, 7.94%.
Compound 36 6,10-Diaza-8 (1,4) -benzena-1,5 (1,4) - diquinolinacyclodecaphane tri-trifluoroacetate. Alternatively named: 1,1'- (Propane-1,3-diyl) -N4, N4'- (p-dimethylenebenzene) -bis- (4-aminoquinoline) tri- trifluoroacetate: This was prepared similarly to Compound 33 from N4, N4' - (p-dimethylenebenzene) -bis- (4-aminoquinolinium) and 1,3-diiodopropane and obtained as a white crystalline solid; mp: 240-242 °C. Analysis for C29H26N4, 3.1 CF3C00H. Calculated: C, 53.93, H, 3.74; N, 7.15%. Found: C, 54.03, H, 3.87; N, 7.34%. Compound 37
6, 13-Diaza-3 (1,3) -benzena-1,5 (1,4) - diquinolinacyclotridecaphane di-trifluoroacetate. Alternatively named: 1,1'- (m-Dimethylenebenzene) -N4, N4'- (hexane-1,6-diyl) -bis- (4-aminoquinolinium) di- trifluoroacetate:
N4, N4'- (Hexane-1, 6-diyl) -bis- (4-aminoquinoline) (0.5 g, 1.35 mmol) and 1, 3-di- (bromomethyl)benzene (0.36 g, 1.35 mmol) in 2-butanone (85 ml) were heated under reflux with stirring for 5 days and then cooled. The resulting precipitate was collected, washed extensively with diethyl ether, and purified by preparative HPLC to give the product as a crystalline solid which was dried in vacuo at 40 °C for 3 days and had mp: 228-230 °C. Analysis for C32H32N4, 2.3 CF3C00H. Calculated:C,
59.82, H, 4.70; N, 7.62%. Found: C, 59.52, H, 4.73; N, 7.59%.
Compound 38 6,12-Diaza-3 (1,3) -benzena-1,5 (1,4) - diquinolinacyclododecaphane di-trifluoroacetate. Alternatively named: 1, 1' - (xn-Dimethylenebenzene) -N4, N4'- (pentane-1,5-diyl) -bis- (4-aminoquinolinium) di- trifluoroacetate: This was prepared similarly to Compound 37 from N4, N4' - (pentane-1, 5-diyl) -bis- (4-aminoquinoline) and 1,3-di- (bromomethyl)benzene and obtained as a white crystalline powder, mp: 238-240 °C. Analysis for C31H30N4, 2.2 CF3COOH. Calculated: C, 59.93, H, 4.57; N, 7.90%. Found: C, 59.91, H, 4.54; N, 7.99%.
Compound 39
6,ll-Diaza-3 (1,3) -benzena-1,5 (1,4) - diquinolinacycloundecaphane di-trifluoroacetate. Alternatively named: 1,1'- (m-Dimethylenebenzene) -N4, N4'- (butane-l,4-diyl) -bis- (4-aminoquinolinium) di- trifluoroacetate:
This was prepared similarly to Compound 37 from N4, N4' - (butane-l,4-diyl) -bis- (4-aminoquinoline) and 1,3-di- (bromomethyl)benzene and obtained as a white crystalline solid, mp: 220-222 °C. Analysis for
C30H28N4, 2.6 CF3COOH. Calculated: C, 57.05, H, 4.16; N, 7.56%. Found: C, 57.04, H, 4.26; N, 7.61%
Compound 40 6,10-Diaza-3 (1,3) -benzena-1,5 (1,4) - diquinolinacyclodecaphane tri-trifluoroacetate. Alternatively named: 1,1'- (m-Dimethylenebenzene) -N4, N4'- (propane-1,3-diyl) -bis- (4-aminoquinolinium) tri- trifluoroacetate: This was prepared similarly to Compound 37 from N4 , N4' (propane-l, 3-diyl) -bis- (4-aminoquinoline) and 1,3-di- (bromomethyl)benzene and obtained as a white crystalline solid, mp: 191-193 °C. Analysis for C29H26N4, 3 CF3C00H. Calculated: C, 54.41, H, 3.78; N, 7.25%. Found: C, 54.57, H, 3.56; N, 7.19%.
Compound 41
8,15-Diaza-l,7(1,4) -diquinolinacyclopentadecaphane di- trifluoroacetate. Alternatively named: 1,1' - (Pentane- 1,5-diyl) -N4, N4'- (hexane-1,6-diyl) -bis- (4- aminoquinolinium) di-trifluoroacetate:
This was similarly prepared from N4, N4' - (hexane-1, 6- diyl) -bis- (4-aminoquinoline) and 1, 5-diiodopentane and obtained as a white crystalline solid, mp: 216-218 °C. Analysis for C29H34N4, 2.2 CF3COOH. Calculated: C, 58.19, H, 5.29; N, 8.13%. Found: C, 58.40, H, 5.41; N, 8.24%.
In order to test the potency of these compounds as SKCa channel blockers, the following method was used.
Preparation of cultured sympathetic neurones
Seventeen-day old Sprague Dawley rats were killed by inhalation of a rising concentration of C02, and the superior cervical ganglia were removed. The ganglia were de-sheathed, cut into small pieces and incubated in Ca2+ and Mg2+ free Hanks's balanced salt solution (Gibco) containing 370 U ml"1 collagenase and 6 mg ml"1 bovine serum albumin at 37°C for 15 min. This was followed by incubation in Hanks's balanced salt solution containing 1 mg ml"1 trypsin and 6 mg ml"1 bovine serum albumin for 30 min. Ganglia were then dissociated using a fire-polished Pasteur pipette, and the resultant cell suspension plated onto laminin coated plastic culture dishes. Cells were grown in L- 15 medium supplemented with 10% foetal calf serum, 0.2 mM glutamine, 0.6%(w/v) D-glucose, 0.19% (w/v) NaHC03, penicillin (100 U ml"1) , streptomycin (100 μg ml"1) and nerve growth factor (mouse submaxillary gland 50 ng ml" x ) . Cells were maintained at 37°C in an atmosphere of 95% 02:5% C02 and are used between 6 hours and 10 days in culture. Inhibition of the afterhvperpolarisation (AHP) of cultured sympathetic neurones
Recording the AHP which follows the action potential in sympathetic neurones provides a indirect relatively simple and convenient means of testing compounds for their ability to block neuronal SKCa channels.
A culture dish was perfused with a solution (hereafter referred to as normal physiological solution) of the following composition (mM) : NaCl 154; KCI 4.7; CaCl2 2.5; MgCl2 1.2; glucose 5.6; HEPES 10 (HEPES is N- (2- hydroxyethyl) piperazine-N' - (2-ethane sulfonic acid) ; adjusted to pH 7.4 with NaOH. Intracellular recordings were made using conventional "*sharp' micro-electrodes filled with 1 M KCI (resistance 80-120 MΩ) connected to the headstage of a Neurolog NL102 amplifier. Action potentials were evoked by injection of a 30 ms depolarizing current pulse every 5 s. The test compounds as synthesised in the example above were applied by bath perfusion for long enough (1-3 min) to cause a steady reduction in the AHP. The extent of the inhibition is expressed as a percentage.
The results are then summarised as an IC50 value, i.e. the concentration of compound required to produce an inhibition of 50%; this is determined by iterative curve fitting and has an associated standard deviation (s.d.) .
Dequalinium has previously shown to be a potent and selective inhibitor of the AHP in sympathetic neurones, with an IC50 of 1 μM [Dunn, P.M (1994. Dequalinium, a selective blocker of the slow afterhyperpolarization in rat sympathetic neurones in culture. European Journal of Pharmacology, 252, 189-194] . In the present study it was slightly more effective with an average IC50 of 0.60 ± 0.05 μM (fitted value ± s.d. data from 17 cells) , and dequalinium was used in each test as an internal standard. Compound A was found to be considerably more active than dequalinium with an ICS0 of 0.08 ± 0.02 μM (fitted value ± s.d. data from 12 cells) . Gallamine is over 100 times less potent than dequalinium, with an IC50 of 68.0 + 8.4 μM (fitted value ± s.d. data from 5 cells) .
The results of the tests are shown in Table 2 below. In this table, the biological activity of each compound is expressed as an IC50 (μM) These values were determined by iterative curve fitting and are given with the approximate standard deviation of the fitted value. The use of dequalinium as a reference compound provides a means of standardising assays carried out at different times, and with preparations of varying sensitivity. This measure of potency is used when relating the biological activity of the new compounds to their chemical structure. A number of compounds show a higher potency than Compound A.
Table 2
Figure imgf000061_0001
Figure imgf000062_0002
Compounds of the invention 42 to 57 made as described below have the structures given by the following structural formula V and Table 3:-
Figure imgf000062_0001
Table 3
Figure imgf000062_0003
Compounds of the invention 58 to 62 also described below have the structures given by the following structural formula VI and Table 4 : -
Figure imgf000063_0001
Table 4
Figure imgf000063_0003
Compounds of the invention 63 and 64 described below have the structures given by the following structural formula VII :
VII
Figure imgf000063_0002
In Compound 63 B is
Figure imgf000064_0001
and in Compound 64 B is (CH, 2)/.5-
Intermediates VII to XII have the structural formula:
Figure imgf000064_0002
wherein A, R and X are given in Table 5
Table 5
Figure imgf000064_0003
Intermediates XIII, XIV, XVIII, XIX, XX have the structural formula:
Figure imgf000065_0001
wherein E, n and X are given in Table 6
Table 6
Figure imgf000065_0002
Next, we describe the preparation of some starting materials and of Intermediates VII to XVII which were themselves used in the synthesis of Compounds 42 to 62 of the invention.
The following known compounds were prepared as starting materials by the method given in respective reference given for each
A. Gabriel; Chem. Ber. : 1981, 24, 1114
Figure imgf000066_0001
bis (2-aminoethyl) sulfide
B. Anikin, V.F.; et. al; Chem. Heterocycl . Compd. (Engl. Transl.) 1982, 18, 193-196
Figure imgf000066_0002
bis (2-aminoethyl) ether
C . Devinsky, F . ; et . al ; Synthesis ; 1980 , 4 , 303 -305
Figure imgf000066_0003
N,N' -dimethyl-pentane-1, 5-diamine
D. Lee, W.W. ; et al; J. Med. Chem.; 1963, 6, 567-569
Figure imgf000067_0001
N,N' -dibenzyl-pentane-1, 5-diamine
E. Sandoz-Wander, Inc., USA; Division of U.S. Patent 3,856,796 (CA 1963,85: 108554)
Figure imgf000067_0002
6- (4-quinolinyl) aminohexan-1-ol
F. Adams,A. et al ; Eur. J. Pharmacol. 1986, 127, 27-35
Figure imgf000067_0003
N,N' -Bis (4-quinolinyl)pentane-1, 5-diamine
Grogan,G CH. et al; J. Org. Chem. 1953, 18, 728-735
Figure imgf000068_0001
Pentan-1, 5-diisothiuronium dibromide
H. Vennerstrom, J.L. et al; J. Med. Chem. 1992, 35, 2119-2134
Figure imgf000068_0002
N,N' -Bis (7-chloroquinolin-4-yl)pentane-1, 5-diamine
Scriabine; Bull. SOc. Chim. Fr. 1947, 455
Figure imgf000069_0001
5-methylaminopentan-l-ol
J. Eliel; et al; J. Org. Chem. 1965, 30 , 2450-2451
Figure imgf000069_0002
5-benzylaminopentan-1-ol 6-benzylaminohexan-l-ol
Intermediate VII Bis [2- (4-quinolinyl)aminoethyl] sulfide,
A mixture of bis (2-aminoethyl) sulfide (starting material A) (2.2 g, 18 mmol) and 4-chloroquinoline (5.9 g, 36 mmol) in pentanol (100 ml) was heated at reflux for 10 h, the cooled and the precipitate was collected by filtration and washed with diethyl ether. The filtration cake was dissolved in hot methanol, basified with IN NaOH solution to pH > 9. After cooling, the precipitate was collected by filtration, washed with water and acetone to give an off-white solid, mp: 148*C.
Analysis for C22H22N4S, 0.3 H20: Calculated: C, 69.55; H, 6.00; N, 14.75%. Found: C, 69.61; H, 6.07; N, 14.68%.
Intermediate VIII
Bis [2- (4-quinolinyl)aminoethyl] ether: A mixture of bis- (2-aminoethyl) ether (starting material B) (1.37 g, 13 mmol) and 4-chloroquinoline (4.3 g, 26 mmol) in pentanol (100 ml) was heated at reflux for 10 h. After cooling, the precipitate was collected by filtration. It was then shaken with IN NaOH aqueous solution and dichloromethane. The organic phase was dried over Na2S04 and evaporated in vacuum to dryness. The residue was crystallised from ethyl acetate to give an off white solid, mp: 182"C.
Intermediate IX
N,N' -Bis (4-quinolinyl) -N,N' -dimethylpentane-1,5- diamine:
A mixture of N,N' -dimethyl-pentane-1, 5-diamine (starting material C) (1.0 g, 7 mmol) and 4- chloroquinoline (2.52 g, 15 mmol) in pentanol (20 ml) was heated at reflux for 24 h. After cooling, diethyl ether was added and the precipitate was collected by filtration. The obtained filtration cake was dissolved in hot methanol, basified with IN NaOH solution to pH> 9. A precipitate was formed and it was collected by filtration, washed with water and acetone to give an off-white solid.
Intermediate X
N,N' -Bis(4-quinolinyl) -N,N' -dibenzylpentane-1,5- diamine:
To a mixture of 4-hydroxyquinoline (1.9 g, 13 mmol) and pyridine (1.0 g, 13 mmol) in CH2Cl2 (20 ml) was added dropwise trifluoromethanesulfonic anhydride at 0 *C. The reaction mixture was stirred at room temperature for 30 min. The precipitate was filtered off and the filtrate was concentrated in vacuum. The obtained residue (1.7 g, 6.1 mmol) and N,N' -dibenzyl-pentane- 1,5-diamine (starting material D) (0.8 g, 2.8 mmol) were dissolved in 2-methoxyethyl ether (20 ml) and was heated at 100 *C for 5 h. After cooling, the reaction mixture was purified by chromatography over a silica gel column using a mixture of CH2Cl2/MeOH/NH4OH (20/1/0.1) as eluant to give a pale yellow product.
Intermediate XI
1,5-Bis(quinolin-4-ylthio) -pentane:
A mixture of S,S' - (pentan-1, 5-yl) -diisothiuronium dibromide (starting material G) (1.32 g, 3.45 mmol) , 4- chloroquinoline (1.13 g, 6.9 mmol) and KOH (0.8 g, 14.0 mmol) in absolute EtOH was heated at reflux for 3 h. The solvent was evaporated and the residue was dispersed in water, extracted with CH2C12. The combined extracts were dried over K2C03. Evaporation of the solvents gave a off-white solid, mp: 107 *C.
Intermediate XII N,N' -Bis (7-trifluoroquinolin-4-yl)pentane-1,5-diamine:
A mixture of 1, 5-diaminopentane (0.51 g, 5 mmol) and 4- chloro-7-trifluoroquinoline (2.32 g, 10 mmol) in phenol (5 g) was heated at 150 *C for 3 h, then cooled and the product was precipitated by diethyl ether. The precipitate was collected by filtration. It was then dissolved in hot methanol, basified with IN NaOH solution to pH > 9. The resulting precipitate was collected by filtration, washed with water and acetone to give an off-white solid, mp: 290*C.
Intermediate XIII
5-Iodo-N- (4-quinolinyl) -pentylamine:
A mixture of 5- (4-quinolinyl) aminopentan-1-ol (0.4 g, 1.7 mmol) and HI (6 ml, 57%) was heated at reflux for 2 h. After cooling, the reaction mixture was diluted by water and the aqueous layer was decanted and rejected. The residue was shaken with CH2C12 and aqueous Na2C03. The organic phase was washed with Na2S203 solution, dried over Na2S04 and evaporated in vacuum to give a white solid.
Intermediate XIV
6-Iodo-N- (4-quinolinyl) -hexylamine: A mixture of 6- (4-quinolinyl)aminohexan-1-ol (starting material E) (1.3 g, 5.3 mmol) and HI (2 ml, 57%) was heated at reflux for 2 h. After cooling, the reaction mixture was diluted with water and the aqueous layer was decanted and rejected. The residue was shaken with CH2C12 and aqueous Na2C03. The organic phase was washed with water, dried over Na2S04 and evaporated in vacuum to give a white solid.
Intermediate XV N-Methyl-N- (4-quinolinyl) -5-aminopentan-l-ol;
A mixture of 5-methylaminopentan-l-ol (starting material I) (0.9 g, 7.7 mmol) and 4-chloroquinoline (1.0 g, 6.1 mmol) was stirred at 150 *C for 4 h. After cooling, the residue was shaken with CH2C12 and aqueous Na2C03. The organic layer was dried and evaporated to give the product as a gummy residue.
Intermediate XVI N-Benzyl-N- (4-quinolinyl) -5-aminopentan-l-01;
A mixture of 5-benzylaminopentan-l-ol (starting material J) (1.7 g, 8.8 mmol) and 4-chloroquinoline (1.0 g, 6.1 mmol) was stirred at 150*C for 4 h. Work¬ up as described for the preparation of intermediate XV gave intermediate XVI as gummy residue. Intermediate XVII N-Benzyl-N- (4-quinolinyl) -6-aminohexan-l-ol;
A mixture of 5-benzylaminohexan-l-ol (starting material J) (1.26 g, 6.1 mmol) and 4-chloroquinoline (1.0 g, 6.1 mmol) was heated at 150"C for 3 h. Work-up as described for the preparation of intermediate XV gave intermediate XVI as a gummy residue.
Intermediate XVIII
5-Iodo-N-methyl-N- (4-quinolinyl) -pentylamine:
To a stirred solution of triphenylphosphine (1.57 g, 6.0 mmol) in toluene (50 ml) was added dropwise a solution of iodine (1.52 g, 6.0 mmol) in toluene (50 ml) at room temperature, then a solution of N-methyl-N- (4-quinolinyl) -5-aminopentan-l-ol (intermediate XV) and triethylamine (0.61 g, 6.0 mmol) was added. The mixture was stirred at room temperature for 3 h. The precipitate was filtered off and the filtrate was chromatographed on a column of silica gel using diethyl ether as eluant. Evaporation of solvents afforded intermediate XVIII as a pale yellow gummy residue.
Intermediate XIX
5-Iodo-N-benzyl-N- (4-quinolinyl) -pentylamine: This was prepared by the same procedure as that described for the preparation of intermediate XVIII, using intermediate XVI .
Intermediate XX
6-Iodo-N-benzyl-N- (4-quinolinyl) -hexylamine:
This was prepared by the same procedure as that described for the preparation of intermediate XVIII, using intermediate XVIII.
In the following syntheses, where preparative high performance liquid chromatography (HPLC) was used, it was carried out with a Gilson apparatus using a UV detector and a Kromasil C18 5 μm column. Solvent mixtures of water + 0.1% trifluoroacetic acid (TFA) and methanol + 0.1% TFA were used with a flow 18 ml/min. In many cases, some excess TFA and H20 were retained in the salts after HPLC.
Compound 42
8,14-Diaza-l,7(1,4) -diquinolina-4-oxa-ll-thiacyclo- tetradecaphanium dibromide sesquihydrate. Alternatively named: 1,1' - [1,5- (3-oxapentan)-diyl]-N,N'-[1,5- (3- thiopentan) -diyl]-bis (4-aminoquinolinium) dibromide sesquihydrate:
Bis [2- (4-quinolinyl) aminoethyl] sulfide (Intermediate VII) (0.75 g, 2.0 mmol) was dissolved in dimethyl formamide (150 ml) at room temperature and bis (2- bromoethyl) ether (0.46 g, 2.0 mmol) added. The mixture was heated at reflux for 48 h. The solvent was then evaporated in vacuum. The residue was crystallised from methanol to give an off-white solid, mp: 307°C dec. Analysis for C26H30Br2N4OS, 1.5 H20:
Calculated: C, 49.30; H, 5.25; N, 8.84%. Found: C, 49.23; H, 5.53; N, 8.84%.
Compound 43
8,14-Diaza-4,ll-dioxa-l,7(1,4) -diquinolinacyclo- tetradecaphanium dibromide dihydrate. Alternatively named: N,N'-[1,5- (3-oxapentan) -diyl]-1,1 ' -[1,5-(3- oxapentan)-diyl]-bis (4-aminoquinolinium) dibromide dihydrate
Bis [2- (4-quinolinyl) aminoethyl] ether (Intermediate VIII) (0.36 g, 1.0 mmol) was dissolved in dimethyl formamide (150 ml) at room temperature and bis (2- bromoethyl) ether (0.23 g, 1.0 mmol) added. The mixture was heated at reflux for 60 h. The solvent was then evaporated in vacuum. The residue was crystallised from methanol to give an off-white solid, mp: 324°C. Analysis for C26H30Br2N4O2, 2 H20: Calculated: C, 49.86; H, 5.47; N, 8.94%. Found: C, 50.17; H, 5.31; N, 8.99%.
Compound 44 8,14-Diaza-ll-oxa-l,7 (1,4) -diquinolinacyclotetradeca- phanium diiodide. Alternatively named: N,N' - [1,5- (3- oxapentan) -diyl] -1,1'- (1,5-pentan-diyl) -bis(4- aminoquinolinium) diiodide Bis [2- (4-quinolinyl) aminoethyl] ether (Intermediate VIII) (0.36 g, 1.0 mmol) was dissolved in dimethyl formamide (150 ml) at room temperature and 1,5- diiodopentane (0.32 g, 1.0 mmol) added. The mixture was heated at reflux for 96 h. The solvent was then evaporated in vacuum. The residue was crystallised from methanol and recrystallised from dimethyl formamide to give a white solid, mp: 311*C. Analysis for C27H32I2N40, 0.4 HI: Calculated: C, 44.21; H, 4.45; N, 7.64%. Found: C, 44.39; H, 4.52; N, 7.56%. Compound 45
8,14-Diaza-ll-oxa-l,7 (1,4) -diquinolina-4- thiacyclotetra-decaphanium di-trifluoroacetate. Alternatively named: N,N' - [1,5- (3-oxapentan) -diyl] - 1,1' - [1,5- (3-thiopentan) -diyl] -bis(4-aminoquinolinium) di-trifluoroacetate:
Bis [2- (4-quinolinyl) aminoethyl] ether (Intermediate VIII) (0.36 g, 1.0 mmol) was dissolved in dimethyl formamide (150 ml) with heating and bis (2-bromoethyl) sulfide (0.25 g, 1.0 mmol) added. The mixture was heated at reflux for 4 days and then the solvent was evaporated in vacuum. The residue was purified by preparative HPLC to give a pale yellow solid, mp: 225*C dec. Analysis for C26H30N4OS2+2CF3CO2 ", 0.5 CF3C02H: Calculated: C, 51.03; H, 4.21; N, 7.68%. Found: C, 51.01; H, 4.23; N, 7.97%.
Compound 46
8,14-Diaza-4-oxa-1,7(1,4)-diquinolinacyclotetradeca- phanium dibromide dihydrate. Alternatively named: 1,1'- [1,5- (3-oxapentan) -diyl] -N,N' - (1,5-pentan-diyl) -bis- (4- aminoquinolinium) dibromide dihydrate N,N' -Bis (4-quinolinyl)pentane-1, 5-diamine (starting material F) (0.36 g, 1.0 mmol) was dissolved in dimethyl formamide (150 ml) at room temperature and bis (2- bromoethyl) ether (0.23 g, 1.0 mmol) added. The mixture was heated to 100*C for 48 h then to reflux for 72 h. The solvent was evaporated in vacuum. The residue was crystallised from iso-propanol then recrystallised from methanol to give an off-white solid, mp: 305*C dec. Analysis for C27H32Br2N40, 2 H20: Calculated: C, 51.94; H, 5.81; N, 8.97%. Found: C, 51.98; H, 5.71; N, 9.02%.
Compound 47
8,14-Diaza-l,7(1,4) -diquinolina-11-thiacyclotetradeca- phanium diiodide. Alternatively named: 1,1' -(1,5- pentan-diyl) -N,N' - [1,5- (3-thiapentan) -diyl] -bis- (4- aminoquinolinium) diiodide
Bis [2- (4-quinolinyl)aminoethyl] sulfide (Intermediate VII) (0.37 g, 1.0 mmol) was dissolved in 4-methyl-2- pentanol (150 ml) with heating and 1, 5-diiodopentane (0.32 g, 1.0 mmol) added. The mixture was heated at reflux for 7 days, then cooled and the precipitate was collected by filtration. Repeated crystallisation from dimethyl formamide/methanol gave a white solid, mp: 290 *C dec. Analysis for C27H32I2N4S, 0.2 HI:
Calculated: C, 51.03; H,. 4.21; N, 7.68%. Found : C , 51 . 01 ; H , 4 . 23 ; N, 7 . 97% .
Compound 48 8,14-Diaza-1,7 (1,4) -diquinolina-4-thiacyclotetradeca- phanium di-trifluoroacetate hemihydrate. Alternatively named: N,N' - (1,5-pentan-diyl) -1,1' - [1,5- (3-thiapentan) - diyl] -bis- (4-aminoquinolinium) di-trifluoroacetate hemihydrate N,N' -Bis (4-quinolinyl)pentane-l, 5-diamine (starting material F) (0.50 g, 1.4 mmol). was dissolved in a mixture of 2-butanone (100 ml) and dimethyl formamide (30 ml) with heating and bis (2-bromoethyl) sulfide (0.35 g, 1.4 mmol) added. The mixture was heated at reflux for 6 days, then cooled and the precipitate was collected by filtration. The crude product was purified by preparative HPLC to give a pale yellow solid, mp: 203'C dec. Analysis for C27H32N4S2+2CF3C02 ", 0.5 H20, 0.5 CF3C02H: Calculated: C, 52.17; H, 4.58; N, 7.61%. Found: C, 52.03; H, 4.94; N, 7.93%.
Compound 49 8,14-Diaza-1,7 (1,4) -diquinolina-4,11-dithiacyclo- tetradecaphanium di-trifluoroacetate. Alternatively named: N,N'- [1,5- (3-thiapentan) -diyl] -1,1' - [1,5- (3- thiapentan) -diyl] -bis- (4-aminoquinolinium) di- trifluoroacetate
Bis [2- (4-quinolinyl) aminoethyl] sulfide (Intermediate VII) (0.74 g, 2.0 mmol) was dissolved in a mixture of
2-butanone (100 ml) and dimethyl formamide (30 ml) with heating and bis (2-bromoethyl) sulfide (0.50 g, 2.0 mmol) added. The mixture was heated at reflux for 5 days and a precipitate was formed. After cooling, the precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 212*C dec.
Analysis for C26H30N4S2 2+2CF3CO2 ", 0.5 CF3C02H: Calculated: C, 49.93; H, 4.12; N, 7.51%. Found: C, 49.28; H, 4.31; N, 7.86%.
Compound 50
8,14-Diaza-8,14-dimethyl-l,7 (1,4) -diquinolinacyclo- tetradecaphanium di-trifluoroacetate trihydrate.
Alternatively named: N,N' -dimethyl-N,N' - (1, 5-pentan- diyl) -1, 1' - (1,5-pentan-diyl) -bis (4-aminoquinolinium) di-trifluoroacetate trihydrate
N,N' -Bis (4-quinolinyl) -N,N' -dimethyl-pentane-1, 5- diamine, (Intermediate IX) (1.7 g, 4.3 mmol) was dissolved in 2-butanone (200 ml) and 1, 5-diiodopentane (1.4 g, 4.3 mmol) added. The mixture was heated at reflux for 7 days. It was cooled and the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 125'C.
Analysis for C30H38N4 2+2CF3CO2 ", 0.8 CF3C02H, 3H20: Calculated: C, 51.77; H, 5.47; N, 6.78%. Found: C, 51.87; H, 5.17; N, 6.71%.
Compound 51
8,14-Diaza-8, 14-dibenzyl-l, 7(1,4) -diquinolinacyclo- tetradecaphanium di-trifluoroacetate monohydrate. Alternatively named: N,N' -dibenzyl-N,N' - (1,5-pentan- diyl) -1, 1' - (1,5-pentan-diyl) -bis(4-aminoquinolinium) di-trifluoroacetate monohydrate
N,N' -Bis (4-quinolinyl) -N,N' -dibenzylpentane-1, 5-diamine (Intermediate X) (0.6 g, 1.1 mmol) was dissolved in 2- butanone (100 ml) and 1, 5-diiodopentane (0.50 g, 1.5 mmol) added. The mixture was heated at reflux for 48 h. After removing half of the solvent, the mixture was heated at reflux for a further 24 h. It was cooled, the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 110'C.
Analysis for C42H46N4 2 +2CF3C02 " , 1 . 8 CF3C02H , 1H20 : Calculated: C, 56.41; H, 4.75; N, 5.30%. Found: C, 56.46; H, 4.86; N, 5.40%.
Compound 52
1,7(1,4) -Diquinolina-8,14-dithiacyclotetradecaphanium di-trifluoroacetate. Alternatively named: S,S'-(1,5- pentan-diyl) -1,1' - (1,5-pentan-diyl) -bis(4- thioquinolinium) di-trifluoroacetate S, S' - (1, 5-Pentan-diyl) -bis (4-thiaquinoline)
(Intermediate XI) (0.7 g, 1.8 mmol) was dissolved in 2- butanone (80 ml) and 1,5-diiodopentane (0.87 g, 2.6 mmol) added. The mixture was heated at reflux for 4 days. It was cooled and the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 182*C. Analysis for C28H32N2S2 2+2CF3C02 ", 0.3 CF3C02H: Calculated: C, 54.31; H, 4.52; N, 3.89%. Found: C, 54.25; H, 4.61; N, 3.85%.
Compound 53
8,14-Diaza-l7,77-ditrifluoromethyl-l,7(l,4) - diquinolinacyclotetradecaphanium di-trifluoroacetate. Alternatively named: N,N' - (1,5-pentan-diyl) -1, 1' - (1,5- pentan-diyl) -bis(4-amino-7-trifluoromethylquinolinium) di-trifluoroacetate
N,N' -Bis (7-trifluoromethylquinolin-4-yl)pentane-1, 5- diamine, (Intermediate XII) (0.49 g, 1.0 mmol) was dissolved in 2-butanone (100 ml) and l, 5-diiodopentane (0.49 g, 1.5 mmol) added. The mixture was heated at reflux for 3 days. It was cooled, the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 234'C. Analysis for C30H32N4 2+2CF3CO2 ", 0.2 CF3C02H: Calculated: C, 50.92; H, 4.00; N, 6.9%. Found: C, 51.08; H, 3.84; N, 6.66%.
Compound 54
8,14-Diaza-l7,77-dichloro-l,7 (1,4) -diquinolinacyclo- tetradecaphanium di-trifluoroacetate sesquihydrate. Alternatively named: N,N' - (1,5-pentan-diyl) -1,1' - (1,5- pentan-diyl) -bis(4-amino-7-chloroquinolinium) di- trifluoroacetate sesquihydrate
N,N' -Bis (7-chloroquinolin-4-yl)pentane-1, 5-diamine (starting material H) (0.43 g, 1.0 mmol) was dissolved in dimethyl formamide (80 ml) and 1, 5-diiodopentane (0.49 g, 1.5 mmol) added. The mixture was heated at 100 *C for 48 h. It was cooled, the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 232 *C (dec) . Analysis for C28H32C12N4 2+2CF3C02 ", 0.9 CF3C02H, 1.5 H20: Calculated: C, 47.70; H, 4.25; N, 6.58%. Found: C, 47.76; H, 4.23; N, 6.66%.
Compound 55
7,13-Diaza-2,3-diene-l,6 (1,4) -diquinolinacyclotrideca- phanium di-trifluoroacetate. Alternatively named: N,N'- (butan-1,2-diene-1,4-diyl) -1,1'- (1,5-pentan-diyl) - bis (4-aminoquinolinium) di-trifluoroacetate N,N' -Bis (4-quinolinyl)pentane-1, 5-diamine (starting material F) (0.35 g, 1.0 mmol) was dissolved in 2- butanone (100 ml) and 1, 4-dichloro-2-butyne (0.12 g, 1.0 mmol) added. The mixture was heated at reflux for 5 days. It was cooled, the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 150'C (dec) . Analysis for C27H28N4 2+2CF3C02 " , 0.6 CF3C02H: Calculated: C, 55.02; H, 4.1; N, 7.97%. Found: C, 55.14; H, 4.35; N, 7.83%.
Compound 56 6,12-Diaza-3 (1,4) -benza-1, 5 (1,4) -di- quinolinacyclododeca-phanium di-trifluoroacetate hemi- hydrate. Alternatively named: 1,1' - (p-xylylene) -N,N' - (1,5-pentan-diyl) -bis (4-aminoquinolinium) di- trifluoroacetate hemihydrate
N,N' -Bis (4-quinolinyl)pentane-1, 5-diamine (starting material F) (0.43 g, 1.0 mmol) was dissolved in a mixture of 2-butanone (50 ml) and dimethyl formamide (10 ml) and a, cn ' -dibromo-p-xylene (0.4 g, 1.5 mmol) added. The mixture was heated at reflux for 3 days. It was cooled, the resulting precipitate was collected by filtration and purified by preparative HPLC to give a white solid, mp: 220*C (dec) .
Analysis for C31H32C12N4 2+2CF3C02 ", 1.0 CF3C02H, 0.5 H20: Calculated: C, 54.89; H, 4.23; N, 6.92%. Found: C, 54.60; H, 4.21; N, 6.92%.
Compound 57
8,13-Diaza-1,7(1,4) -diquinoline-10- ynecyclotridecaphanium di-trifluoroacetate. Alternatively named: 1,1' - (1, 5-pentan-diyl) ) -N,N' - (but- 2-yne-1,4-diyl) -bis (4-aminoquinolinium) di- trifluoroacetate:
To a mixture of 4-hydroxyquinoline (2.0 g, 13.8 mmol) and pyridine (1.1 g, 14.0 mmol) in CH2Cl2 was added dropwise a solution of trifluoromethanesulfonic anhydride at 0*C. After addition, the reaction mixture was stirred at room temperature for 30 min. The precipitate produced was filtered off and the filtrate was concentrated in vacuum to give a pale yellow oil . It was dissolved in 20 ml of 2-methoxyethyl ether and but-2-yne-l,4-diamine (Johnson: J. Chem. Soc. 1946; 1012) (0.25 g, 3.0 mmol) was added. The mixture was stirred at 100'C for 24 h. After cooling the precipitate generated was collected by filtration, washed with acetone to give a solid, mp : 210°C. This solid is N,N' -Bis (4-quinolinyl) -but-2-yne-l, 4-diamine.
N,N' -Bis (4-quinolinyl) -but-2-yne-l,4-diamine (0.28 g, 0.83 mmol) was dissolved in a mixture of 2-butanone (50 ml) and dimethyl formamide (10 ml) with heating and 1, 5-diiodopentane (0.28 g, 0.86 mmol) added. The mixture was heated at reflux for 5 days. After cooling, the precipitate produced was collected by filtration and purified by preparative HPLC to give a white solid, mp: 226"C dec. Analysis for C27H28N4 2+2CF3C02- , 0.16 CF3C02H: Calculated: C, 57.62: H, 4.35; N, 8.58%. Found: C, 57,56; H, 4.33; N, 8.60%.
Compound 58 8,16-Diaza-l(l,4) ,9(4,1)- diquinolinacyclohexadecaphanium di-trifluoroacetate dihydrate. Alternatively named: 1,N' - (1,6-hexan-diyl) - N,1' - (1,6-hexan-diyl) -bis (4-amino quinolinium) di- trifluoroacetate dihydrate
6-Iodo-N- (4-quinolinyl) -hexylamine (Intermediate XIV) (1.7 g, 4.8 mmol) was dissolved in a mixture of 2- butanone (90 ml) and dimethyl formamide (30 ml) . The mixture was heated at reflux for 5 days, then cooled and the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 203 'C dec.
Analysis for C30H38N4 2+2CF3CO2 ", 0.5 CF3C02H, 2 H20: Calculated: C, 54.33; H, 5.54; N, 7.24%. Found: C, 54.17; H, 5.55; N, 7.31%.
Compound 59
7,14-Diaza-l(l,4) ,8(4,1)- diquinolinacyclotetradecaphanium di-trifluoroacetate dihydrate. Alternatively named: 1,N' - (1,5-pentan-diyl) - N,l' - (1,5-pentan-diyl) -bis (4-amino-quinolinium) di- trifluoroacetate dihydrate
5-Iodo-N- (4-quinolinyl) -pentylamine (Intermediate XIII) (0.52 g, 1.5 mmol) was dissolved in a mixture of 2- butanone (40 ml) and dimethyl formamide (3 ml) . The mixture was heated at reflux for 4 days, then cooled and the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 209'C dec.
Analysis for C28H34N4 2+2CF3C02 ", 0.4 CF3C02H, 2 H20: Calculated: C, 56.42; H, 4.97; N, 8.02%. Found: C, 56.24; H, 4.93; N, 8.00%.
Compound 60 7,14-Diaza-7,14-dimethyl-l(l,4) ,8(4,1) - diquinolinacyclo-tetradecaphanium di-trifluoroacetate. Alternatively named: N,N' -dimethyl-1,N' - (1, 5-peιitan- diyl) -N,1' - (1,5-pentan-diyl) -bis(4-aminoquinolinium) di-trifluoro-acetate 5-Iodo-N-Methyl-N- (4-quinolinyl) -pentylamine Intermediate XVIII) (0.8 g, 2.3 mmol) was dissolved in 2-butanone (80 ml) . The solution was heated at reflux for 4 days, then cooled and the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 205 "C dec. Analysis for C30H38N4 2+2CF3CO2 ", 0.8 CF3C02H: Calculated: C, 55.39; H, 5.07; N, 7.26%. Found: C, 55.38; H, 5.24; N, 7.37%.
Compound 61
7,14-Diaza-7,14-dibenzyl-l(1,4) ,8 (4,1) diquinolinacyclo-tetradecaphanium di-trifluoroacetate. Alternatively named: N,N' -dibenzyl-l,N' - (1, 5-pentan- diyl) -N,1' - (1, 5-pentan-diyl) -bis(4-aminoquinolinium) di-1rifluoroacetate 5-Iodo-N-benzyl-N- (4-quinolinyl) -pentylamine
(Intermediate XIX) (0.5 g, 1.2 mmol) was dissolved in 2-butanone (80 ml) . The solution was heated at reflux for 3 days, then cooled and the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 145"C. Analysis for C42H4eN4 2+2CF3C02 " , 2 CF3C02H: Calculated: C, 56.78; H, 4.60; N, 5.35%. Found: C, 56.61; H, 4.56; N, 5.28%.
Compound 62
8,16-Diaza-8,16-dibenzyl-l(l,4) ,9(4,1)- diquinolinacyclo-hexadecaphanium di-trifluoroacetate. Alternatively named: N,N' -dibenzyl-l,N' - (1,6-hexan- diyl) -N,1' - (1,6-hexan-diyl) -bis (4-aminoquinolinium) di- trifluoroacetate
6-Iodo-N-benzyl-N- (4-quinolinyl) -hexylamine (Intermediate XX) (1.5 g, 3.4 mmol) was dissolved in 2- butanone (90 ml) . The solution was heated at reflux for 5 days, then cooled and the resulting precipitate was collected by filtration and purified by preparative HPLC to give a pale yellow solid, mp: 175 *C dec. Analysis for C44H50N4 2't'2CF3CO2 " , 1.3 CF3C02H: Calculated: C, 60.22; H, 5.17; N, 5.55%. Found: C, 60.10; H, 5.14; N, 5.47%.
Compound 63 l3,53-Diamino-6,10-diaza-3 (1,3) , 8 (1,4) -dibenza-
1,5(1,4) -dipyridinacyclodecaphanium dibromide. Alternatively named: 1,1' - (m-xylylene) -N4, N4'-(p- xylylene) -bis(3,4-diaminopyridinium) dibromide N,N' -Bis (3-aminopyridin-4-yl) -xylene-α, a' -diamine (0.12 g, 0.38 mmol) and a, a' -dibromo-m-xylene (0.10 g, 0.38 mmol) was dissolved with heating in pentan-1-ol (65 ml) . The solution was heated at reflux for 6 days with stirring. During the course of the reaction a creamy precipitate was formed. After cooling, the solid was collected by vacuum filtration. The brown solid was washed with methanol and dried in vacuo (100 *C) and a hygroscopic beige solid was obtained, mp: 355*C. Analysis for C26H28N6 2+2Br" , 0.3 C5Hι;LOH, 0.5 H20: Calculated: C, 53.29; H, 5.30; N, 13.56%. Found: C, 53.19; H, 5.00; N, 13.19%. Compound 64 l3,73-Diamino-2, 6-diaza-4 (1,4) -benza-1,7 (4,1)- dipyridina-cyclododecaphanium diiodide methanolate. Alternatively named: 1,1' - (pentan-1, 5-diyl) -N4, N4'-(p- xylylene) -bis (3,4-diaminopyridinium) diiodide methanolate
N,N' -Bis (3-aminopyridin-4-yl) -xylene-α, a' -diamine (0.15 g, 0,47 mmol) and 1, 5-diiodopentane (0.15 g, 0.47 mmol) was dissolved with heating in pentan-1-ol (60 ml) . The solution was heated at reflux for 6 days with stirring. During the course of the reaction a brown precipitate was formed. After cooling, the solid was collected by vacuum filtration. The brown solid was washed with methanol and dried in vacuuo (100 *C) to yield a beige solid, mp: 290'C.
Analysis for C23H30N6 2+2I" , 1.0 CH3OH, 0.4 H20: Calculated: C, 42.17; H, 5.13; N, 12.24%. Found: C, 41.86; H, 4.80; N, 12.06%.
The biological potency of some of these compounds was assessed by their ability to reduce the amplitude of the after-hyperpolarization (AHP) recorded from rat superior cervical ganglion cells in short term tissue culture, using the technique described in detail above. The results are in Table 7 Table 7
Figure imgf000094_0001
Proposed use in the treatments of disorders A local injection of apamin, which acts at the same K+ channel and in the same way as the compounds of the present invention, reduces spontaneous and evoked electrical activity in the muscle of patients with myotonic muscular dystrophy [Behrens, M I., Jalil, P., Serani, A., Vergara, F. and Alvarez, 0. (1994) . Possible role of apamin-sensitive K+ channels on myotonic dystrophy. Muscle & nerve, 17: 1264 - 1270] . However, apamin' s central neurotoxicity rules out its systemic use; the compounds of the present invention are likely to be more selective in their action in reducing the hyperexcitability associated with this condition.
The inventors have found that compounds of the present invention, by blocking SKCa channels, increase the amplitude of peristalsis in intestinal smooth muscle at unprecedently low concentrations for a low molecular weight synthetic compound. The EC50 values for Compound 24 and Compound 10 are 0.5 nM and 1 nM respectively, as tested on isolated rabbit jejunum. This shows that the compounds of the present invention may act as a novel prokinetic agent for the treatment of gastrointestinal dysmotilities. The parenteral administration of very small doses of apamin has been shown to facilitate memory processes involved in task learning in mice [Messier, c, Mourre, C, Bontempi, B., Sif, J. , Lazdunski. M. and Destrade, C. (1991) . Effect of apamin, a toxin that inhibits Ca2+- dependent K+ channels, on learning and memory processes. Brain Research, 551: 332 - 336; Belcadi- Abbassi, W. and Destrade, C. (1995) . Post-test apamin injection suppresses a Kamin-like effect following a learning session in mice. Neuroreport . 6: 1293-1296] . The compounds of the present invention are likely to exert the same action as apamin in the treatment of disorders of memory, but with greater selectivity.
Narcolepsy and associated disorders are associated with the premature onset of rapid-eye-movement (REM) sleep. Intraventricularly-administered apamin produces a dose- dependent reduction in REM sleep expression in rats [Benington, J. , Woudenberg, M.C. and Heller, H.C. (1995) . Apamin, a selective SK channel blocker, suppresses REM sleep without a compensatory rebound. Brain Research, 692: 86 - 92] . The compounds of the present invention are likely to exert the same action as apamin, but with greater selectivity.
It has been suggested that dequalinium and other lipophilic cationic compounds are likely to have anticarcinoma activity [Weiss et . al . , Proc. Natl. Acad. Sci. USA. 1987, 8±, 5444-8. Gamboa-Vujicic et. al, J. Pharm. Sci. 1993, 82, 231. Helige et . al, Eur. J. Cancer, 1993, 29A, 124.] The compounds of the present invention are likely to exert similar action, but with greater selectivity.
The intracerebro-ventricular injection of apamin has been found to inhibit ethanol-induced narcosis in mice [Yamamoto, H.-A. and Harris, R. A. (1983) . Calcium- dependent 86Rb efflux and ethanol intoxication: studies of human red blood cells and rodent brain synaptosomes. Eur. J. Pharmacol. 88: 357 - 363] providing behavioural evidence for the importance of SKCa channels in alcohol- induced coma and raising the possibility that SKCa blockers could be of value in its treatment. The compounds of the present invention are likely to exert the same action as apamin, but with greater selectivity.
Dequalinium is commonly found as an antibacterial agent, particularly in throat lozenges and similar preparations. It is therefore expected that the compounds of the present invention would exhibit antibacterial properties and could be used in medicaments, e.g. throat lozenges, swabs, as such.
It is thought that the compounds of the present invention will exhibit selectivity between different types of SKCa channels. This may be due to some feature of the structure of the compounds of the present invention conferring the ability to discriminate between the different types of channel.
It should be understood that embodiments of the present invention have been described above by way of example only and various alternative modifications from what has been specifically described and illustrated can be made within the scope of the invention, as will be readily apparent to persons skilled in the art.

Claims

1. A compound having the general formula I or II:
Figure imgf000099_0001
or any one of its conjugate bases where: each Q" is the conjugate base of a pharmaceutically acceptable inorganic or organic acid;
Rx is selected from H and
Figure imgf000099_0002
R5 being selected from H, and substituents such as a halogen, an alkyl group with 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group;
R2 and R3 are independently selected from H, and substituents such as a halogen, an alkyl group with 1 to
10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group; R is selected from H and Rc
Figure imgf000100_0001
R6 being selected from H, and substituents such as a halogen, an alkyl group with 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group; where R2, R3, R5 and R6 may be present once or a plural number of times on the respective rings; each X is independently selected from NH, NR7, O, S and CH2, R7 being selected from alkyl, aryl, alkaryl and aralkyl groups having 1 to 10 carbon atoms;
A and B which are the same or different, are each selected from a spacing group with a chain length of 3 to 15 atoms; except that in general formula I when
Figure imgf000100_0002
R2 and R3 are H, X is NH, and A is (CH2)10,
B cannot be
Figure imgf000100_0003
2. A compound according to claim 1 which has the general formula I and in which
(i) each R2, R3, R5 and R6 is independently selected from H, a halogen, an alkyl group with 1 to 10 carbon atoms, an amino group, an alkylamino group, a hydroxy group and an alkoxy group, and (ii) each X is selected from NH, 0, S and CH2.
3. A compound according to claim 1 or 2, wherein X is
NH.
4. A compound according to claim 1, 2 or 3 , wherein
R 1 and R4 are R ,5 " <€>
^
Figure imgf000101_0001
respectively.
5. A compound according to claim 4, wherein R5 and R6 are both H.
6. A compound according to claim 5, wherein R2 and R3 are both H.
7. A compound according to any one of claims 1 to 6, wherein A and B are independently selected from: -(CH2)n- where n=3~10;
- (CH2)m-Z- (CH2)m wherein Z is O or S and each m is 1 to 5; a straight chain alkene or alkyne containing one or two C=C or C≡≡C bonds respectively and having 3 to 10 carbon atoms;
Figure imgf000102_0001
Figure imgf000102_0002
where D is joined to the rings in the meta or para positions, and is selected from (CH2)k where k=0-2, CH=CH, C≡C and a heterocyclic ring;
Figure imgf000102_0003
where E and E' are selected from (CH2)k where k=0-2 and CH=CH; and one or more of the aromatic rings in A and B may be substituted by one or more of the groups OH, alkoxy and halogen.
8. A compound according to claim 7, wherein A and B are independently selected from :
-(CH2)n- where n=3-8;
- (CH2)m-Z- (CH2)m wherein Z is O or S and each m is 1 to 3 ; a straight chain alkene or alkyne containing one or two C=C or C≡C bonds respectively and having 3 to 6 carbon atoms;
0
Figure imgf000103_0001
where the groups are meta or para to each other and where the ring is optionally substituted by one or more of the groups OH, methoxy and halogen;
Figure imgf000103_0002
where D is selected from (CH2)k where k=0 or 1, CH=CH, and a pyridine ring attached to the rings at the two sites ortho to the N atom; and
^ ^
Figure imgf000103_0003
where E is CH2 and E' is a direct link between the rings .
9. A compound according to claim 8, wherein A is selected from -(CH2)n-, where n=3-6,
-CH 2 0 - "C-H2—
and
Figure imgf000103_0004
and B is selected from -(CH2)n where n=4-6,
Figure imgf000104_0001
and
R7 —CH2—rpVCH2—
where R7 is selected from H, OH, OMe.
10. A method for producing a compound according to any one of claims 1 to 9 having the general formula I, by reacting a compound of the general formula:
Figure imgf000104_0002
with a compound of the formula
H2N - A - NH2 to give
Figure imgf000104_0003
which is then further reacted with a compound of the formula
Z - B - Z to give
Figure imgf000104_0004
or any one of its conjugate bases, where Y and Z are independently selected from a sulphonate, CI, Br and I.
11. A method for producing a compound according to any one of claims 1 to 9 having the general formula I, by reacting a compound of the general formula
Figure imgf000105_0001
with a compound of the general formula Z - B - Z to give
Figure imgf000105_0002
where Z is selected from Cl, Br and I.
12. A method of producing a compound according to any one of claims 1 to 9 having the general formula II, by reacting a compound of the general formula III
Figure imgf000105_0003
with a compound of the general formula IV
Figure imgf000105_0004
to give
Figure imgf000106_0001
where Y and Z are independently selected from Cl, Br and I.
13. A method according to claim 12 wherein compounds III and IV are the same compound.
14. The use of a compound according to any one of claims 1 to 9 or Compound A in the treatment of myotonic muscular dystrophy, gastrointestinal dysmotility, a disorder of memory, narcolepsy or an associated disorder, a cancer, ethanol-induced neurotoxicity, or bacterial infection.
15. The use of a compound according to any one of claims 1 to 9 or Compound A in the preparation of a pharmaceutical for the treatment of myotonic muscular dystrophy, a gastrointestinal dysmotility, a disorder of memory, narcolepsy or an associated disorder, a cancer, or ethanol-induced neurotoxicity.
16. The use of a compound according to any one of claims 1 to 9 or Compound A in the preparation of an antibacterial agent.
17. A pharmaceutical composition containing a compound according to any one of claims 1 to 9 or Compound A.
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