Neurological disorders, for which the present compounds are useful, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia. The compounds useful in the present invention are believed to act by binding to the [3H]-emopamil binding site of sterol isomerase and thereby inhibiting the activity thereof.

Background [3H]-Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al., Mol. Pharmacol. 43: 139-148,1993). Moebius et al. termed this site the"anti-ischaemic"binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents. In liver, the [3H]-emopamil binding site is localised to the endoplasmic reticulum.

Emopamil and ifenprodil are neuroprotective compounds that exhibit high affinity for the [3H]-emopamil binding site. However these compounds are not selective inhibitors and exhibit activity either at neuronal voltage-sensitive calcium channels (VSCC), the polyamine site of the N-methyl-D-aspartate (NMDA) receptor and/or the sigma-1 binding site.

The efficacy of emopamil as a neuroprotective agent is considered to be most likely derived from action at either the VSCC or 5-HTz receptors. Inconsistent with this hypothesis is the observation that verapamil, although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially thought to be due to lack of CNS penetration further studies suggest other factors may be involved (Keith et al., Br. J. Pharmacol. 113: 379-384, 1994).

Description of the Invention It has now been found that the emopamil binding protein corresponds to sterol isomerase and that compounds in accord with structural diagram I that selectively bind to emopamil binding protein have the property of inhibiting the action of sterol isomerase. Such compounds are considered useful for the therapeutic treatment of animals including man, in particular for the treatment of neurological disorders such as stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia.

Accordingly, one aspect of the invention provides compounds according to structural diagram I I wherein: Rl and R3 are selected from benzyl, phenethyl, naphthylmethyl, Cl 8alkyl, C3 6cycloalkylClalkyl and CH3SC1-4alkyl ; R2 and R4 are independently selected from hydrogen, benzyl, Cl 8alkyl and C3-6cycloalkylC1-4alkyl,and any phenyl ring of said benzyl or phenethyl is unsubstituted or substituted at one or two positions with a moiety selected from halo, C1-4alkyl and C1-4alkoxy or a pharmaceutically- acceptable salt of any such compound with the proviso that in any compound according to structural diagram I R2 and R4 are not both hydrogen, orthochlorophenyl or cyclobutylmethyl.

Particular compounds of the invention are those wherein: R'and R3 are benzyl, and R and Ruz are independently selected from hydrogen, benzyl, C1-8alkyl and C3-6cycloalkylC1-4alkyl.

Other compounds of the invention are those wherein:

R'and R3 are selected from benzyl, phenethyl, naphthylmethyl, Cl 8alkyl, C3-6cycloalkylC1-4alkyl and CH3SC1-4alkyl; any phenyl ring of said benzyl or phenethyl is unsubstituted or substituted at one or two positions with a moiety selected from chloro, fluoro, methyl and methoxy, and R2 and R4 are methyl.

Still other compounds of the invention are those wherein: Rl and R3 are selected from benzyl, phenethyl, naphth-1-ylmethyl, naphth-2-ylmethyl, Cl- 6alkyl, cyclohexylmethyl and CH3SC] 3alkyl ; any phenyl ring of said benzyl or phenethyl is unsubstituted or substituted at one or two positions with a moiety selected from chloro, fluoro, methyl and methoxy, and R'and R'are methyl.

Yet other compounds of the invention are those wherein: Rl and R3 are selected from benzyl, phenethyl, naphth-1-ylmethyl, naphth-2-ylmethyl, n-hexyl, n-pentyl, 3-methyl-n-butyl, cyclohexylmethyl and CH3$ (CH2) 3 ; any phenyl ring of said benzyl or phenethyl is unsubstituted or substituted at one or two positions with a moiety selected from chloro, fluoro, methyl and methoxy, and R2 and R4 are methyl.

Most particular compounds of the invention are those disclosed in the Examples described herein.

The class of compounds according to structural diagram I, as described above, show selective action at the [3H]-emopamil binding site and are believed to be neuroprotective without acting at either VSCC or NMDA receptors. Accordingly, such compounds will therefore have fewer associated side effects such as hypotension which is seen with emopamil or the behavioural manifestations seen with ifenprodil..

It will be understood by those of skill in the art that certain compounds of the structural diagram I can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. Therefore, it is to be understood that the invention encompasses any such solvated and unsolvated forms. Further, the invention further relates to and encompasses any tautomeric forms of compounds according to structural diagram I.

A second aspect of the present invention provides a process for preparing a compound of structural diagram I as defined herein or a pharmaceutically-acceptable salt thereof which process comprises: preparing an intermediate by process a) or b) and reacting said intermediate according to process c) or d) to form said compound according to structural diagram I, wherein: a) comprises reacting a compound of structural diagram II with a compound of structural diagram III according to the following scheme:

to form a compound of structural diagram IV wherein CO-R in combination is a moiety that upon reduction is converted to an R or an R moiety as heretofore defined, and thereafter reducing said compound of structural diagram IV to form a compound of structural diagram V; b) comprises reacting a compound of structural diagram It with a compound of structural diagram VI according to the following scheme:

to form a compound of structural diagram VII wherein R6 can be a variety of moieties selected from ethyl, propyl, t-butyl or the like, and thereafter reducing said compound of structural diagram VII to form a compound of structural diagram VIII ; c) comprises alkylating a compound of structural diagram V according to the following scheme:

v I to form a compound of structural diagram I wherein R is any moiety corresponding to R3 as defined herein, and d) comprises reacting a compound of structural diagram V according to the following reductive amination scheme:

V I to form a compound of structural diagram I wherein the moiety R and R'in combination is any moiety corresponding to R3 as defined herein; and thereafter if necessary, i) converting a compound of the structural diagram I into another compound of the structural diagram I ; ii) removing any protecting groups, or

iii) forming a pharmaceutically-acceptable salt.

It will be appreciated by those of skill in the art that in some of the reactions described herein it may be necessary or desirable to protect sensitive groups in the compounds or their precursors. Conventional protecting groups may be used in accordance with standard practice.

Such practice is described in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment'with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.

Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

A third aspect the invention comprises a method for using compounds of structural diagram I for the treatment of neurological disorders such as stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia. In this aspect of the invention compounds according to structural diagram I can be used for the prophylactic or therapeutic treatment of mammals including humans.

To use a compound of the structural diagram I or a pharmaceutically-acceptable salt thereof for the prophylactic or therapeutic treatment of mammals including humans, such a compound would be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Such pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, sterile aqueous or oily solutions or suspensions or sterile emulsions and as formulations for parenteral use as by an intravenous, intramuscular or infusion route.

Compounds of the present invention may be simultaneously or sequentially co- administered with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.

A fourth aspect of the invention comprises pharmaceutical compositions, as further disclosed herein, comprising compounds of structural diagram I in association with one or more pharmaceutically-acceptable excipients, diluents, carriers or stabilisers.

Pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.

In another aspect of the present invention there is provided a compound of the structural diagram I or a pharmaceutically-acceptable salt thereof, as defined herein for use in a method of treatment of the human or animal body.

Yet another aspect of the present invention provides a compound of structural diagram I or a pharmaceutically-acceptable salt thereof, for use as a medicament to inhibit the [3H]- emopamil binding site in a warm-blooded animal such as a human being.

Still another aspect of the invention provides the use of a compound of the structural diagram I, or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of the [3H]-emopamil binding site in a warm-blooded animal such as a human being.

Yet another aspect of the invention provides a method of inhibiting of the [3H]- emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment, which method comprises administering to said animal an effective amount of a compound of structural diagram I or a pharmaceutically-acceptable salt thereof, as defined herein.

The following Biological Test Methods, Data and Examples serve to illustrate but not limit the present invention.

Biological Test Methods 3H-Emopamil binding to guinea pig liver membranes The method of (-)- [3H]-emopamil binding was a modification of Zech, C., Staudinger R., Muhlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines : characterisation of a

sodium-sensitive drug receptor with (-)- [3H]-emopamil. Eur. J. Pharm. 208: 119-130, 1991.

Guinea Pig liver membranes have emopamil binding sites and such membranes may be used to measure the ability of a compound to inhibit the binding of (-)- [3H]-emopamil binding to such sites. The concentration of test compound required to inhibit the binding of (- )-[3H-emopamil allows determination of the affinity of the compound for the binding site.

Guinea-pig liver membrane preparation: Male guinea pigs were sacrificed by CO2 asphyxiation with dry ice. The livers were quickly excised and weighed and rinsed in membrane preparation buffer containing 10 mM Hepes, 1 mM Tris base-EDTA, 250 mM sucrose, pH 7.4. The livers were then minced, homogenised in 10 times volume with a motor driven Teflon-glass homogeniser with three strokes on ice. The homogenate was centrifuged at 1000 x g in a SS34 rotor for 5 minutes at 4 °C. The supernatant was filtered through 4 layers of gauze and then centrifuged at 8000 x g for 10 minutes at 4 °C. This resulting supernatant was centrifuged at 40,000 x g for 15 minutes at 4 °C. The resulting pellet was resuspended in assay buffer and centrifuged again at 40,000 x g for 15 minutes at 4 °C. This pellet was resuspended in assay buffer (2.5 fold with respect to original wet weight) and homogenised by one stroke with a Teflon-glass homogeniser. Aliquots of 1 ml were stored at-70 °C.

Assay Reaction Mixture : Assay reaction tubes contained the following: Assay buffer: 10 mM Tris-HCI, 0.1 mM phenylmethylsulphonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4 °C.

Radioligand : 0.96 nM (-)- [3H]-emopamil (Amersham).

Guinea pig liver membranes: 40mg/mL original wet weight.

Test compounds: 1-300 nM.

Total volume: 500 u. l.

This mixture was incubated for 60 minutes at 37 °C. The incubation was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenimine (PEI) and washed three times with 5 ml of wash buffer containing 10 mM Tris-HCI, 10 mM MgCl2, 0.2% BSA, pH 7.4 at 25 °C. Specific binding was defined with 10 VM emopamil. In general compounds with an ICsobelow 300 nM in this test were of interest.

3H-D-888 binding to rat brain cortical membranes The method of 3H-D-888 binding was a modification of Reynolds, I. J., Snowman, A. M. and Synder, S. H. (-)- [3H] Desmethoxyverapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. 237 : no. 3,731-738,1986.

Rat brain cortical membranes express calcium channel receptors which bind the ligand D-888. The ability of a compound to block the binding of 3H-D-888 measures the ability of such a compound to bind to such calcium channel receptors. Thus, inhibition of 3H-D-888 binding, or lack thereof, allows the specificity of the compound for emopamil binding sites to be assessed.

Rat brain cortical membrane preparation Male Sprague-Dawley Rats were sacrificed by decapitation and the brains were quickly excised. The cerebellum and brain stem were removed and discarded; and the rest of the brain was rinsed in 320 mM sucrose. The brain was then homogenised in a 10-fold volume of 320 mM sucrose with a motor driven Teflon-glass homogeniser using 10 strokes on ice.

The homogenate was spun at 1000 x g for 10 minutes at 4 °C in a SS-34 rotor. The supernatant was then spun at 29,000 x g for 20 minutes. The resulting pellet was resuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4) to a final concentration of 60 mg original wet weight/ml.

Assay Reaction Mixture: Assay tubes contained the following: Assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4 Radioligand: llM 3H-D888 (Amersham) Rat cortical membranes: 6 mg/ml original wet weight Test compounds: 0.3-100 uM Total volume : 1000 Rl This mixture was incubated for 60 minutes at 25 °C. The assay was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenimine (PEI) and washed three times with 5 ml of wash buffer containing 20 mM Hepes, 20 mM MgCl2, pH 7.4. Specific binding was measured with 10 lM methoxyverapamil (D-600). This assay was used to determine in vitre selectivity of

compounds vs. type voltage sensitive calcium channels, i. e. high affinity for the 3H-D888 binding site would show a lack of selectivity.

Examples The invention is now illustrated but not limited by the following Examples in which. unless otherwise stated:- (i) concentrations were carried out by rotary evaporation in vacuo ; (ii) operations were carried out at ambient temperature, that is in the range 18-26 °C and under a nitrogen atmosphere; (iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385) ; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structure of the end-products of the structural diagram I were generally confirmed by NMR and mass spectral techniques-proton magnetic resonance spectra were determined in DMSO-Sg using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (8 scale) and peak multiplicities are shown thus: s, singlet; bs, broad singlet; d, doublet; AB or dd, doublet of doublets; t, triplet, dt, double of triplets, m, multiplet; bm, broad multiplet and unless otherwise stated lu NMR is quoted; (vi) TLC's were monitored on silica gel plates: Silica Gel GHLF (Analtech), 250 microns, plates (2. 5. x 10 cm). The detection methods used were UV light, iodine, and iodoplatinate.

(vii) Kugelrohr distillation was using apparatus supplied by Aldrich Chemical Co; it is bulb-to-bulb short path distillation; the air bath temperature at which the material distils is denoted as the boiling point; (viii) intermediates were not generally fully characterised and purity was in general assessed mass spectral (MS) or NMR analysis; (ix) Solvents were dried over magnesium sulphate (MgS04) ; and (x) the following abbreviations (also used hereinabove) may be used:- DMSO is dimethylsulphoxide; CDC13 is deuterated chloroform ; THF is tetrahydrofuran ; DCM is dichloromethane;

TLC is thin layer chromatography ; EA is Elemental Analysis; and DMAC is dimethyl acetamide.

Example 1. trans-NX-Bis (phenylmethyl)-14-cyclohexanediamine : The title intermediate was prepared as follows: to a solution of trans-1, 4- diaminocyclohexane (3.0 g, 26.3 mmol) in 100 mL of CH2C12 in a flask was fitted with a reflux condenser was added triethylamine (13.2 mL, 94.7 mmol). The mixture was then cooled to 0 °C in an ice bath and benzoyl chloride (9.8 mL, 84.1 mmol) was added dropwise.

A thick white precipitate formed and when addition was complete, the mixture was allowed to stir at room temperature. After 24 h, the reaction mixture was filtered and the residue was washed with water and ether. The residue was then ground to a fine powder and dried in vacuo at 40 °C for 24 h. The yield was 8.72g.

To a suspension of the powder from the previous step (3.0 g, 9.30 mmol) in 60 mL of THF in a flask was added lithium aluminum hydride (1.44 g, 37, 2 mmol). Additional THF was added to rinse the lithium aluminum hydride into the flask. The reaction mixture was heated to reflux for 22 h, then cooled to room temperature and quenched with solid Na2S04. 1OH20. The mixture was stirred until all the salts had turned white filtered through diatomaceous clay and solvents were removed from the filtrate to yield a white solid.

Purification by silica gel chromatography (20: 1 CH2CI2/2MNH3 in MeOH) yielded the title compound as a white solid (2.19 g, 80%).

Example 2. trans-NN'-Bis (phenelmethvl !-NN'-dimethyl 4-cyclohexanediamine : To a solution of trans-N, N-bis (phenylmethyl)-1, 4-cyclohexanediamine (1.27 g, 4.32 mmol) in 43 mL of THF was added triethylamine (2.53 mL, 18. 1 mmol), followed by ethyl chloroformate (907 mL, 9.49 mmol). A white precipitate immediately formed. After 3 h, the reaction appeared incomplete by MS analysis, and another 907 mL of ethyl chloroformate was added. After an additional 30 min, the reaction mixture was added to saturated NaHCO3 solution (50 mL) and ether (50 mL). The aqueous layer was extracted with ether (1 x 50 mL).

The combined organic layers were washed with sequentially with water (1 x 100 mL) and brine (1 x 100 mL) and dried over Na2S04. Removal of solvents yielded a white liquid which was purified by silica gel chromatography (1: 1 hexane/EtOAc) to afford a white solid.

To a solution of the white solid from the previous step (1.70 g, 3.88 mmol) in 25 mL of THF was added lithium aluminum hydride (589 mg, 15.5 mmol) and the suspension was heated to reflux for 2.5 h. The reaction mixture was then cooled to room temperature and solid Na2SO4. 1 OH20 was added. When the reaction was completely quenched, the mixture was dried with anhydrous MgS04 and then filtered through diatomaceous clay. Solvents were removed to yield the title compound as a white solid which was purified by silica gel chromatography (20: 1 CH2C12/2MNH3 in MeOH) to afford a crystalline white solid (996 mg, 71%).'HNMR (300 MHz, d6-DMSO): d 7. 30 (m, 10H), 3.55 (s, 4H), 2.41 (m, 2H), 2.19 (s, 6H), 1.97 (m, 4H), 1.34 (m, 4H). m/s: (M+1) + = 323.

Example 3. trans-N, N-Bis (phenvlmethrl)-N, N-di-n-propyl-1, 4-cyclohexanediamine : To a solution of trans-NN-bis (phenylmethyl)-1, 4-cyclohexanediamine, see Example 1, (109 mg, 0.370 mmol) in 1 mL of DCE was added propionaldehyde (52 mL, 0.721 mmol) and then glacial acetic acid (40 mL, 0.700 mmol). A thick white precipitate immediately formed. Additional DCE (2 mL) was added to aid stirring and sodium cyanoborohydride (216 mg, 1.02 mmol) was then added. The reaction mixture was stirred for 20 h at room temperature and then added to saturated NaHCO3 solution (5 mL) and extracted with EtOAc (3 x 5 mL). The ether extracts were washed with brine (1 x 10 mL) and dried over Na2S04.

Removal of solvents yielded a white crystalline solid which was purified by silica gel chromatography (3: 1 hexane/EtOAc then 1: 1 hexane/EtOAc) to afford the title compound (129 mg, 92%).'H NMR (300 MHz, CDC13) : d 7.29-7.18 (m, 10H), 3.53 (s, 4H), 2.34 (m, 6H), 1.77 (m, 4H), 1.29 (m, 8H), 0.76 (m, 6H). m/s: (M+1) + = 379.

Table 1 shows the compounds of Examples 2 and 3, above, and compounds of Examples 4 through 17 inclusive. Table 1 also shows the nanomolar (nM) affinity of such compounds for the emopamil binding sites of guinea pig liver membranes (ECP) and the affinity of certain such compounds for D-888 binding sites of rat brain cortical membranes (D888). Compounds of Example 3,4,5,9,13,14 and 15 were made from the compound of Example I by the procedure and technique described in Example 3 using a suitable precursor in place of propioaldehyde. The compounds of Examples 6,7,8,10,11 and 12 were made from the compound of Example 18 by the procedure and technique described in Example 3.

Compounds of Example 16 and 17 were made by the procedure and technique of Example 3. The structure of each product was confirmed by NMR and MS analysis and compounds were determined to have a purity generally greater than seventy-five percent.

Table 1 : Ex. No. Name ECP D888 M* (nM) (nM) 2 trans-N,N'-Bis(phenylmethyl)-N,N'-dimethyl-1,4- 25 13378 B cyclohexanediamine 3 trans-N,N'-Bis(phenylmethyl)-N,N'-di-n-propyl-1,4- 23 11255 C cyclohexanediamine 4 trans-N, N-Bis (phenylmethyl)-N-cyclohexylmethyl-1, 4- 30 C cyclohexanediamine 5 trans-N,N'-Bis(phenylmethyl)-N,N'-bis[(3-methylthio)- 30 C 1-propyl]-1, 4-cyclohexanediamine 6 trans-N, N-Bis (phenylethyl)-N, N'-dimethyl-1, 4- 20 C cyclohexanediamine trans-N, N-Di (n-hexyl)-N, N'-dimethyl-1, 4-6 C cyclohexanediamine 8 trans-N, N-Bis (cyclohexylmethyl)-N, N'-dimethyl-1, 4- 22 C cyclohexanediamine 9. trans-N, N-Bis (phenyhnethyl)-N, N'-di (n-pentyl)-1, 4- 48 C cyclohexanediamine 10 trans-N, N'-Bis (3-methyl-1-butyl)-N, N'-dimethyl-1, 4-90 C cyclohexanediamine 11 trans-N, lV-Dimethyl-N, N'-di (n-pentyl)-l, 4-93 C cyclohexanediamine 12 trans-N,V-Bis [ (3-methylthio)-l-propyl]-N, N'-dimethyl- 103 C 1,4-cyclohexanediamine 13 trans-N, N-Bis (phenylmethyl)-N, N'-bis (3-methyl-1- 142 C butyl)-1, 4-cyclohexanediamine 14 trans-N,N'-Bis(phenylmethyl)-N,N'- >300 C dicyclohexylmethyl-1,4-cyclohexanediamine 15 trans-N, N-Bis (phenylethyl)-N, N'-bis (phenylmethyl)- 71 C 1,4-cyclohexanediamine 16 trans-N, N, N'-Tris (phenylmethyl)-1, 4-22 1334 C cyclohexanediamine 17 trans-N, N, N'-Tris (phenylmethyl)-N'-methyl-1, 4- 50 40647 cyclohexanediamine

M* B-made by the methods of Example 1 and Example 2; C-made by the methods of Example 1 and Example 3.

Example 17. trans-NNN'-Tris (phenvlmethyl)-N'-methyl-v l4-cyclohexanediamine : The title compound was prepared from the compound of Example 16, as follows. A solution of trans-N,N,N'-tris(phenylmethyl)-1, 4-cyclohexanediamine, Example 16, (65 mg, 0.169 mmol) in 5 mL of methanol was treated with formaldehyde (37 wt % in water, 329 mL, 4.39 mmol). A white precipitate immediately formed. After 5 h, sodium borohydride (121 mg, 3.21 mmol) was added in small portions and stirring was continued overnight. After 24 h, the reaction mixture was added to water (15 mL) and CtI2C12 (15 mL). The aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic layers were washed with water (1 x 20 mL) and brine (1 x 20 mL) and dried over Na2S04. Removal of solvents yielded a white residue. Purification by silica gel chromatography (1 : 1 hexane/ethyl acetate) yielded the title compound as a white solid (52 mg, 77%).'H NMR (300 MHz, CDC13) : d 7.35-7.17 (m, 15H), 3.56 (s, 4H), 3.48 (s, 2H), 2.38 (m, 2H) ? 2.03 (s, 3H), 1.19 (m, 4H), 1.42 (m, 2H), 1. 19 (m, 2H). m/s: (M+H) += 399.

Example 18. trans-N,N'-dimethyl-1,4-cyclohexanediamine : The title intermediate was prepared as follows. To a solution of trans-1, 4- diaminocyclohexane (10.3. g, 90.2 mmol) in 450 mL of THF at 0 °C was added triethylamine (51 mL, 366 mmol) followed by ethyl chloroformate (18.4 mL, 192 mmol). A white precipitate formed and when addition was complete the reaction was allowed to stir at room temperature overnight. The mixture was then added to saturated NaHCO3 solution (300 mL) and ether (200 mL). The layers were separated and the aqueous layer was extracted with ether

(2 x 300 mL). The combined organic layers were washed sequentially with water and brine.

Removal of solvents yielded an off-white solid gel which was dried in vacuo.

The solid gel from the previous step was dissolved in 600 mL of THF and treated with lithium aluminum hydride (8.6 g, 226 mmol) and the mixture heated to reflux for 1 h. The reaction was then quenched with solid Na2SO4. 1OH20. When all the solids had turned white, the mixture was stirred for an additional 6 h. MeOH (2 mL) was added to quench any remaining lithium aluminum hydride. The mixture was then filtered over diatomaceous clay.

Removal of solvents yielded the title compound as a white semisolid (11.3 g, 88%).

Example 19. trans-N*Nl-bisEt4-Chlorophenvl ! methyll-N dimethyl-l4 cyclohexanediamine: To a suspension of the white semisolid from Example 18 (104 mg, 0.731 mmol) in 5 mL of THF was added 4-chlorobenzyl chloride (444 mg, 2.76 mmol), followed by potassium carbonate (388 mg, 2.81 mmol) and the reaction mixture was heated to reflux for 5 h. The reaction mixture was then added to water (5 mL) and CH2C12 (5 mL). The aqueous layer was then extracted with CH2C12 (1 x 5 mL) and the combined organic layers were dried over Na2S04. Removal of solvents yielded a yellow liquid. Purification by silica gel chromatography (20: 1 CH2Cl2/2MNH3 in MeOH) yielded the title compound as a white solid (50 mg, 17%).'H NMR (300 MHz, CDC13) : d 7.26 (m, 8H), 3.51 (s, 4H), 2. 40 (m, 2H), 2.17 (s, 6H), 1.93 (m, 4H), 1.32 (m, 4H). m/s : (M+1) + = 391,393.

Table 2 shows the compound of Example 19 and compounds of Example 20 through 30. Table 2 also shows the nanomolar (nM) affinity of such compounds for the emopamil binding sites of guinea pig liver membranes (ECP) and the affinity of certain such compounds for D-888 binding sites of rat brain cortical membranes (D888). Compounds 20 through 30 shown in Table 2 were made from suitable trans-1, 4-cyclohexanediamine precursors by the procedures and techniques described in Example 29 utilizing suitable precursors in place of 4- chlorobenzyl chloride. The structure of each compound was confirmed by NMR and MS analysis and compounds were determined to have a purity generally greater than seventy-five percent.

Table 2 : Ex. No. Name ECP D888 M* (nM) (nM) 19 trans-N,N'-Bis[(4-chlorophenyl)methyl]-N,N'-dimethyl- 63 D 1,4-cyclohexanediamine 20 trans-N, N-Bis [ (3-fluorophenyl) methyl]-N, N'-dimethyl- 24 9771 D I,4-cyclohexanediamine 21 trans-N, N-Bis [ (3-methylphenyl) methyl]-N, N'-dimethyl- 31 D 1,4-cyclohexanediamine 22 trans-N,N'-Bis[(4-fluorophenyl)methyl]-N,N'-dimethyl- 31 4990 D 1,4-cyclohexanediamine 23 trans-N, N-Bis [ (4-methylphenyl) methyl]-N, N'-dimethyl- 53 D 1,4-cyclohexanediamine 24 trans-N,N'-Bis[(2-methylphenyl)methyl]-N,N'-dimethyl- 61 5523 D 1,4-cyclohexanediamine 25 trans-N, N-Bisj (3, 4-dichlorophenyl) methyl]-NN'- 61 D dimethyl-1,4-cyclohexanediamine 26 trans-N,N'-Bis[(naphth-1-yl)methyl]-N,N'-dimethyl-1,4- 73 2052 D cyclohexanediamine 27 trans-N, N'-Bis [(2-fluorophenyl) methyl]-N, N'-dimethyl-104 D 1,4-cyclohexanediamine 28 trans-N, N'-Bis [(4-methoxyphenyl) methyl]-N, N'-159 D dimethyl-1,4-cyclohexanediamine 29 trans-N, N'-Bis [(naphth-2-yl) methyl]-N, N'-dimethyl-1, 4-289 D cyclohexanediamine 30 trans-N,N,N',N'-Tetra[(phenyl)methyl]-1,4- 221 D cyclohexanediamine

Example 31 Following conventional procedures well known in the pharmaceutical art the following representative pharmaceutical dosage forms containing a compound of structural

diagram I can be prepared: (a) Tablet mg/tablet Compound of structural diagram I 50.0 Mannitol, USP 223.75 Croscarmellose sodium 60 Maize starch 15.0 Hydroxypropylmethylcellulose (HPMC), USP 2.25 Magnesium stearate 3.0 (b) Capsule mg/capsule Compound of structural diagram I 10.0 Mannitol, USP 488. 5 Croscarmellose sodium 15.0 Magnesium stearate 1.5 (c) Injectectable For injectable administration such as by an intravenous route, a compound of structural diagram I is prepared as an isotonic sterile solution (5 mg/ml).