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

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. Of these, 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. 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 SK _Ca 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 SK _Ca 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 SK _Ca channel heterogeneity.

DISCLOSURE OF THE INVENTION

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:

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

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 ,

B cannot be

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, R ¹ and R ⁴ are

- _£ ? _\ and R ² and R ³ are H.

When any of 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. Some suitable substituents are given above. Others are such as acyl, -CH, etc.

Compounds which have shown greater potency for blocking SK _Ca channels are where A is selected from -(CH ₂ ) _n -, where n=3-6,

and

and B is selected from -(CH ₂ ) _n - where n=4-6,

and

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

and B is

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 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.

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:

wiith a compound of the formula H: ₂ N - A - NH to give

which is then further reacted with a compound of the formula Z - B - Z to give

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

with a compound of the general formula

Z - B - Z to give

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

with a compound of the general formula IV

to give

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 CH ₃ OH and H ₂ 0.

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 CH ₃ OH, EtOH is C ₂ H ₅ OH, DMF is dimethyl formamide.

The structures of the Compounds 1 to 41 of the invention can all be represented by the general formula:

An alternative structural representation is

which illustrates the conjugate base.

Groups A and B are detailed in Table 1 for each of Compounds 1 to 41.

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 C ₂₈ H ₃₄ N ₄ , 0.3 CH ₃ OH, 0.2 H ₂ 0. 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) -N ⁴ , N ⁴ ' , 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 C ₄₂ H ₄₄ N ₄ , 3.4 CF ₃ COOH, 1.4 H ₂ 0. 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) - N ⁴ , N ⁴ '-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 C ₄₂ H ₄₄ N ₄ , 4.2

CF ₃ COOH, 2.2 H ₂ 0. 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) - N ⁴ , N ⁴ '-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 C ₄₃ H ₄₄ N ₄ , 3.9 CF ₃ COOH, 2 H ₂ 0.

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) -N ⁴ ,N ⁴ '-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 C ₄₃ H ₄₆ N ₄ , 3.2 CF ₃ COOH, 1.2 H ₂ 0. 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,p ^f - dimethylene- (Z) -stilbene) -N ⁴ ,^ 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 C ₄₄ H ₄₆ N ₄ , 4.2 CF ₃ COOH, 2.2 H ₂ 0. 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-CHCl ₃ -petroleum ether (bp 40-60 °C) and dried to give 1.5 g; mp: 250- 252 °C dec. Analysis for C ₃₂ H _2e N ₄ , 0.8 CH ₃ 0H. 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- N ⁴ ,!! 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 C ₄₂ H ₄₄ N ₄ , 3.1 CF ₃ C00H, 1.1 H ₂ 0. 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) -N ⁴ ,N ⁴ '- (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 C ₄₆ H ₃₆ N ₄ , 6 CF ₃ COOH, 4 H ₂ 0. 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 C ₂₆ H ₂₂ N ₄ , 1.7 H ₂ 0. 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 C ₃₄ H ₂₈ N ₄ , 2 CF ₃ COOH, 2.4 H ₂ 0. 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) - N ⁴ ,N ⁴ '- (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 C ₃₄ H ₂₈ N ₄ , 2 CF ₃ C00H, 1.1 H ₂ 0. 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 C ₂₆ H ₂₂ N ₄ , 0.4 H ₂ 0. 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^N ⁴ '- (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 C ₃₄ H ₂₈ N ₄ , 3 CF ₃ COOH, H ₂ 0. Calculated: C, 56.34, H, 3.90; N, 6.57%. Found:C, 56.72, H, 4.21; N, 6.42%.

Compound 11

3 ² -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) -N ⁴ ,N ⁴ '- (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 (MgS0 ₄ ) 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 C ₃₄ H ₂₈ N ₄ 0, 3 HBr, CH ₃ 0H. Calculated: C, 53.66, H, 4.50; N, 7.15%. Found: C, 53.56, H, 4.54; N, 6.86%.

Compound 12

3 ² -Hydroxy-3 ⁵ -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) -N ⁴ ,!* 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 C ₃₄ H ₂₇ IN ₄ 0, 2 HI, CH ₃ 0H, 0.5 H ₂ 0. Calculated: C, 45.14, H, 3.68; N, 6.01%. Found: C, 45.37, H, 3.62; N, 5.60%.

Compound 13

3 ² -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) -N ⁴ ,!! 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 C ₃₅ H ₃₀ N ₄ O, 2 HBr, 2 H ₂ 0.

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' jN ⁴ ,!! 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 C ₃₄ H ₂₈ N ₄ , 3 CF ₃ C00H, 1.2 H ₂ 0. 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:CHCl ₃ =l :1) to give a yellowish powder; this was dissolved in dry 2-propanol, filtered, and dried; mp: 116-118 °C (decomp) . Analysis for C ₃₃ H ₂₈ N ₄ , 2.3 CH ₃ 0H, 0.1 H ₂ 0. 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' jN ⁴ ,!! 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 C ₄₈ H ₄₀ N ₄ , 3 CF ₃ C00H, 2.2 H ₂ 0. 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) -N ⁴ ,N ⁴ '- (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 C ₄₈ H ₄₀ N ₄ , 4 CF ₃ COOH, 2 H ₂ 0. 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) -N ⁴ ,*! 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 C ₄₈ H ₄₀ N ₄ , 2 CF ₃ COOH, 3.4 H ₂ 0. 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] -N ⁴ ,N ⁴ ' ^" (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 C ₅₂ H ₄₀ N ₅ , 3 CF ₃ COOH, 2 CH ₃ OH, 2.8 H ₂ 0. 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, CHC1 ₃ , petroleum ether (bp: 60-80 °C) ] was obtained as cream crystals; mp: 250-252 °C (decomp) . Analysis for C ₂₆ H ₂₂ N ₄ , 1.6 H ₂ 0. 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) -N ⁴ ,N ⁴ '- (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 C ₄₈ H ₄₀ N ₄ , 4.5 CF ₃ C00H, 7 H ₂ 0. 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) -N ⁴ ,N ⁴ '- (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 C ₄₇ H ₃₆ N ₄ , 4 CF ₃ COOH, 6.6 H ₂ 0.

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) -N ⁴ ,!* 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 N ⁴ , N ⁴ '- (octane-1, 8-diyl) -bis- (4-aminoquinoline) as a white crystalline solid (0.6 g, 98% yield) ; mp: 185- 189 °C.

A mixture of N ⁴ , N ⁴ '- (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 C ₃₄ H ₄₆ N ₄ I ₂ , 1.5 H ₂ 0. 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) -N ⁴ , N ⁴ '- (decane-1,10-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate.

A mixture of N ⁴ , N ⁴ '- (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 C ₃₈ H ₅₂ N ₄ , 3 CF ₃ C00H. 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) -N ⁴ , N ⁴ '- (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 N ⁴ , N ⁴ '- (hexane-1, 6-diyl) -bis- (4- aminoquinoline) as a white crystalline solid (0.55 g, 97% yield) ; mp: 226-230 °C.

A mixture of N ⁴ , N ⁴ '- (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 C ₃₀ H ₃₆ N ₄ , 4 CF ₃ C00H. 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) -N ⁴ , N ⁴ '- (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 N ⁴ , N ⁴ '- (pentane-1, 5-diyl) -bis- (4-aminoquinoline) as a white crystalline solid, mp: 204-208 °C. A mixture of N ⁴ , N ⁴ '- (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 C ₂₈ H ₃₂ N ₄ , 4.2 CF ₃ COOH. 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) -N ⁴ , N ⁴ '- (pentane-1,5-diyl) -bis- (4- aminoquinolinium) di-trifluoroacetate:

This was prepared similarly to Compound 24 from N ⁴ , N ⁴ ' - (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 C ₂₇ H ₃₀ N ₄ , 2.3 CF ₃ COOH. 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) -N ⁴ , N ⁴ '- (pentane-1,5-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate:

This was prepared similarly to Example 24 from N ⁴ , N ⁴ ' - (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 C ₂₉ H ₃₆ N ₄ , 3.1 CF ₃ C00H. 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) -N ⁴ , N ⁴ '- (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 N ⁴ , N ^4' - (butane-l,4-diyl) -bis- (4-aminoquinoline) as a white crystalline solid; mp: 258-264 °C.

A mixture of N ⁴ , N ⁴ ' - (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 C ₂₆ H ₂₈ N ₄ , 4.1 CF ₃ COOH. 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) -N ⁴ , N ⁴ '- (butane-l,4-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate:

This was prepared similarly to Compound 27 from N ⁴ , N ⁴ '- (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 C ₂₇ H ₃₀ N ₄ , 2.7 CF ₃ COOH. 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) -N ⁴ , N ⁴ ' - (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 N ⁴ , N ⁴ ' - (propane-1, 3-diyl) -bis- (4-aminoquinoline) , as a white crystalline solid; mp: 302-306 °C.

A mixture of N ⁴ , N ⁴ '- (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 C ₂₆ H ₂₈ N ₄ , 3.2 CF ₃ COOH. 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) -N ⁴ , N ⁴ '- (propane-1,3-diyl) -bis- (4-

aminoquinoquinolinium) tri-trifluoroacetate:

From N ⁴ , N ⁴ '- (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 C ₂₅ H _2G N ₄ , 3.4 CF ₃ COOH. 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) -N ⁴ , N ⁴ '- (propane-1,3-diyl) -bis- (4- aminoquinolinium) tri-trifluoroacetate: This was prepared in a similar manner to Compound 29 from N ⁴ , N ⁴ ' - (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 C ₂₄ H ₂₄ N ₄ , 3.2 CF ₃ COOH. 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 C ₂₄ H ₂₄ N ₄ , 3.2 CF ₃ C00H, 0.5 H ₂ 0. 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) -N ⁴ , N ⁴ '- (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 N ⁴ , N ⁴ ' - (p-dimethylenebenzene) -bis (4-aminoquinoline) as a pale yellow solid; mp: 278-280 °C(dec) .

A mixture of N ⁴ , N ⁴ ' - (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 C ₃₁ H ₃₀ N ₄ , 2.2 CF ₃ COOH. 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) -N ⁴ , N ⁴ ' (p-dimethylenebenzene) -bis- (4- aminoquinoline) ditrifluoroacetate sesquihydrate: This was prepared in a similar manner to Compound 33 from N ⁴ , N ⁴ '- (p-dimethylenebenzene) -bis- (4- aminoquinolinium) and 1,4-diiodobutane and obtained as a white crystalline solid; mp: 248-250 °C(dec) . Analysis for C ₃₀ H ₂₈ N ₄ , 2 CF ₃ COOH, 1.5 H ₂ 0. 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) -N ⁴ , N ⁴ '- (p- dimethylenebenzene) -bis- (4-aminoquinolinium) di- trifluoroacetate:

This was similarly prepared from N ⁴ , N ⁴ '-(p- dimethylenebenzene) -bis- (4-aminoquinolinium) and 1,6- diiodohexane and obtained as a white crystalline solid; mp: 251-253 °C. Analysis for C ₃₂ H ₃₂ N ₄ , 2.2 CF ₃ C00H. 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) -N ⁴ , N ⁴ '- (p-dimethylenebenzene) -bis- (4-aminoquinoline) tri- trifluoroacetate: This was prepared similarly to Compound 33 from N ⁴ , N ⁴ ' - (p-dimethylenebenzene) -bis- (4-aminoquinolinium) and 1,3-diiodopropane and obtained as a white crystalline solid; mp: 240-242 °C. Analysis for C ₂₉ H ₂₆ N ₄ , 3.1 CF ₃ C00H. 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) -N ⁴ , N ⁴ '- (hexane-1,6-diyl) -bis- (4-aminoquinolinium) di- trifluoroacetate:

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. Analysis for C ₃₂ H ₃₂ N ₄ , 2.3 CF ₃ C00H. 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) -N ⁴ , N ⁴ '- (pentane-1,5-diyl) -bis- (4-aminoquinolinium) di- trifluoroacetate: This was prepared similarly to Compound 37 from N ⁴ , N ⁴ ' - (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 C ₃₁ H ₃₀ N ₄ , 2.2 CF ₃ COOH. 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) -N ⁴ , N ⁴ '- (butane-l,4-diyl) -bis- (4-aminoquinolinium) di- trifluoroacetate:

This was prepared similarly to Compound 37 from N ⁴ , N ⁴ ' - (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

C ₃₀ H ₂₈ N ₄ , 2.6 CF ₃ COOH. 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) -N ⁴ , N ⁴ '- (propane-1,3-diyl) -bis- (4-aminoquinolinium) tri- trifluoroacetate: This was prepared similarly to Compound 37 from N ⁴ , N ⁴ ' (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 C ₂₉ H ₂₆ N ₄ , 3 CF ₃ C00H. 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) -N ⁴ , N ⁴ '- (hexane-1,6-diyl) -bis- (4- aminoquinolinium) di-trifluoroacetate:

This was similarly prepared from N ⁴ , N ⁴ ' - (hexane-1, 6- diyl) -bis- (4-aminoquinoline) and 1, 5-diiodopentane and obtained as a white crystalline solid, mp: 216-218 °C. Analysis for C ₂₉ H ₃₄ N ₄ , 2.2 CF ₃ COOH. 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 SK _Ca 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 C0 ₂ , and the superior cervical ganglia were removed. The ganglia were de-sheathed, cut into small pieces and incubated in Ca ²⁺ and Mg ²⁺ 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) NaHC0 ₃ , 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% 0 ₂ :5% C0 ₂ 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 SK _Ca 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; 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 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 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 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 IC ₅₀ 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 IC _S0 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 IC ₅₀ 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

Compounds of the invention 42 to 57 made as described below have the structures given by the following structural formula V and Table 3:-

Table 3

Compounds of the invention 58 to 62 also described below have the structures given by the following structural formula VI and Table 4 : -

Table 4

Compounds of the invention 63 and 64 described below have the structures given by the following structural formula VII :

VII

In Compound 63 B is

and in Compound 64 B is (CH, 2)/ _. 5-

Intermediates VII to XII have the structural formula:

wherein A, R and X are given in Table 5

Table 5

Intermediates XIII, XIV, XVIII, XIX, XX have the structural formula:

wherein E, n and X are given in Table 6

Table 6

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

bis (2-aminoethyl) sulfide

B. Anikin, V.F.; et. al; Chem. Heterocycl . Compd. (Engl. Transl.) 1982, 18, 193-196

bis (2-aminoethyl) ether

C . Devinsky, F . ; et . al ; Synthesis ; 1980 , 4 , 303 -305

N,N' -dimethyl-pentane-1, 5-diamine

D. Lee, W.W. ; et al; J. Med. Chem.; 1963, 6, 567-569

N,N' -dibenzyl-pentane-1, 5-diamine

E. Sandoz-Wander, Inc., USA; Division of U.S. Patent 3,856,796 (CA 1963,85: 108554)

6- (4-quinolinyl) aminohexan-1-ol

F. Adams,A. et al ; Eur. J. Pharmacol. 1986, 127, 27-35

N,N' -Bis (4-quinolinyl)pentane-1, 5-diamine

Grogan,G CH. et al; J. Org. Chem. 1953, 18, 728-735

Pentan-1, 5-diisothiuronium dibromide

H. Vennerstrom, J.L. et al; J. Med. Chem. 1992, 35, 2119-2134

N,N' -Bis (7-chloroquinolin-4-yl)pentane-1, 5-diamine

Scriabine; Bull. SOc. Chim. Fr. 1947, 455

5-methylaminopentan-l-ol

J. Eliel; et al; J. Org. Chem. 1965, 30 , 2450-2451

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 C ₂₂ H ₂₂ N ₄ S, 0.3 H ₂ 0: 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 Na ₂ S0 ₄ 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 CH ₂ Cl ₂ (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 CH ₂ Cl ₂ /MeOH/NH ₄ OH (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 CH ₂ C1 ₂ . The combined extracts were dried over K ₂ C0 ₃ . 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 CH ₂ C1 ₂ and aqueous Na ₂ C0 ₃ . The organic phase was washed with Na ₂ S ₂ 0 ₃ solution, dried over Na ₂ S0 ₄ 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 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.

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 CH ₂ C1 ₂ and aqueous Na ₂ C0 ₃ . 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 H ₂ 0 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 C ₂₆ H ₃₀ Br ₂ N ₄ OS, 1.5 H ₂ 0:

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 C ₂₆ H ₃₀ Br ₂ N ₄ O ₂ , 2 H ₂ 0: 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 C ₂₇ H ₃₂ I ₂ N ₄ 0, 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 C ₂₆ H ₃₀ N ₄ OS ²⁺ 2CF ₃ CO ₂ ^" , 0.5 CF ₃ C0 ₂ H: 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 C ₂₇ H ₃₂ Br ₂ N ₄ 0, 2 H ₂ 0: 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 C ₂₇ H ₃₂ I ₂ N ₄ S, 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 C ₂₇ H ₃₂ N ₄ S ²⁺ 2CF ₃ C0 ₂ ^" , 0.5 H ₂ 0, 0.5 CF ₃ C0 ₂ H: 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 C ₂₆ H ₃₀ N ₄ S ₂ ²⁺ 2CF ₃ CO ₂ ^" , 0.5 CF ₃ C0 ₂ H: 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 C ₃₀ H ₃₈ N ₄ ²⁺ 2CF ₃ CO ₂ ^" , 0.8 CF ₃ C0 ₂ H, 3H ₂ 0: 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 C ₄₂ H ₄₆ N ₄ ^{2 +} 2CF ₃ C0 ₂ ^" , 1 . 8 CF ₃ C0 ₂ H , 1H ₂ 0 :

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 C ₂₈ H ₃₂ N ₂ S ₂ ²⁺ 2CF ₃ C0 ₂ ^" , 0.3 CF ₃ C0 ₂ H: 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-l ⁷ ,7 ⁷ -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 C ₃₀ H ₃₂ N ₄ ²⁺ 2CF ₃ CO ₂ ^" , 0.2 CF ₃ C0 ₂ H: 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-l ⁷ ,7 ⁷ -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 C ₂₈ H ₃₂ C1 ₂ N ₄ ²⁺ 2CF ₃ C0 ₂ ^" , 0.9 CF ₃ C0 ₂ H, 1.5 H ₂ 0: 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 C ₂₇ H ₂₈ N ₄ ²⁺ 2CF ₃ C0 ₂ ^" , 0.6 CF ₃ C0 ₂ H: 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 C ₃₁ H ₃₂ C1 ₂ N ₄ ²⁺ 2CF ₃ C0 ₂ ^" , 1.0 CF ₃ C0 ₂ H, 0.5 H ₂ 0: 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 CH ₂ Cl ₂ 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 C ₂₇ H ₂₈ N ₄ ²⁺ 2CF ₃ C0 ₂ - , 0.16 CF ₃ C0 ₂ H: 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 C ₃₀ H ₃₈ N ₄ ²⁺ 2CF ₃ CO ₂ ^" , 0.5 CF ₃ C0 ₂ H, 2 H ₂ 0: 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 C ₂₈ H ₃₄ N ₄ ²⁺ 2CF ₃ C0 ₂ ^" , 0.4 CF ₃ C0 ₂ H, 2 H ₂ 0: 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 C ₃₀ H ₃₈ N ₄ ²⁺ 2CF ₃ CO ₂ ^" , 0.8 CF ₃ C0 ₂ H: 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 C ₄₂ H _4e N ₄ ²⁺ 2CF ₃ C0 ₂ ^" , 2 CF ₃ C0 ₂ H: 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 C ₄₄ H ₅₀ N ₄ ^2't' 2CF ₃ CO ₂ ^" , 1.3 CF ₃ C0 ₂ H: Calculated: C, 60.22; H, 5.17; N, 5.55%. Found: C, 60.10; H, 5.14; N, 5.47%.

Compound 63 l ³ ,5 ³ -Diamino-6,10-diaza-3 (1,3) , 8 (1,4) -dibenza-

1,5(1,4) -dipyridinacyclodecaphanium dibromide. Alternatively named: 1,1' - (m-xylylene) -N ₄ , N ₄ '-(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 C ₂₆ H ₂₈ N ₆ ²⁺ 2Br ^" , 0.3 C ₅ H _ι;L OH, 0.5 H ₂ 0: Calculated: C, 53.29; H, 5.30; N, 13.56%. Found: C, 53.19; H, 5.00; N, 13.19%.

Compound 64 l ³ ,7 ³ -Diamino-2, 6-diaza-4 (1,4) -benza-1,7 (4,1)- dipyridina-cyclododecaphanium diiodide methanolate. Alternatively named: 1,1' - (pentan-1, 5-diyl) -N ₄ , N ₄ '-(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 C ₂₃ H ₃₀ N ₆ ²⁺ 2I ^" , 1.0 CH ₃ OH, 0.4 H ₂ 0: 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

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 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) . Effect of apamin, a toxin that inhibits Ca ²⁺ - 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 ⁸⁶ Rb 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 SK _Ca channels in alcohol- induced coma and raising the possibility that SK _Ca 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 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.

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.