The present invention relates to compound and compositions for use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission.

The excitatory neurotransmission underlying brain fonction is primarily (about 80 per cent) dependent on the action of glutamate and other related neurotransmitters on specific receptors activated by the excitatory amino acids. These receptors fall into several categories, one of which is the glutamate receptor specifically sensitive to the agonist N-methyl-D-aspartate (the NMDA receptor). NMDA receptor subtypes are ubiquitously expressed in mammalian brain and have unique properties underlying their role in synaptic fonction and plasticity. In view of the central role of these receptors in normal central nervous system fonction, numerus suggestions have been made as to the utility of drugs acting at this receptor to modulate the processes underlying various disease states. The NMDA receptor has been studied with particular interest in relation to its apparent involvement in the pathophysiology of neurodegenerative diseases.

Non-competitive antagonists at this receptor should be particularly advantageous in the treatment of diseases since such compound would have activity that should not be overcome by high levels of endogenous agonists and would act equally well independent of the endogenous agonist activating the receptor. This is important since high levels of endogenous glutamate can occur in certain pathological processes and there are a variety of different endogenous agonists that can act through a variety of specific modulatory agonist binding sites on the receptor.

A number of NMDA antagonists have been disclosed which operate by binding to the ion-channel of the NMDA receptor. The avantage of channel blockers is that they operate only on the"open"channel and therefore do not affect unactivated receptors. In addition they are effective regardless of the mechanism of receptor stimulation and their effect will not be diminished by large concentrations of endogenous agonis.

Given that the NMDA receptor plays a primary role in normal central nervous system function, it is not surprising that certain drugs acting to block or antagonise the function of this receptor affect normal fonction within the brain. This may be manifeste as central nervous system side effects such as hallucinations, confusion, paranoia, aggression, agitation and catatonia. These side effects can be described as a psychotic state and the drugs that induce them are known as psychotomimetic NMDA antagonists.

Such side effects limit the utility of these compound in treating disease states. NMDA receptor antagonists that have efficacy in treating central nervous system disorders but without such psychotomimetic side effects would have a clear therapeutic avantage.

Thugs, yin view of the crucial role played by the NMDA receptor in either the progression or expression of the disease pathology and process, it is an object of this invention to provide compound for the treatment of central nervous system disorders which modulate the activity of the NMDA receptor but which are well-tolerated in the sense of having a markedly reduced propensity to induce psychotomimetic side effects.

The present invention is particularly concerne with the treatment of neurodegenerative disorders. There is a large body of evidence to suggest that either an excitotoxic or slow excitotoxic pathological over-activation of the NMDA receptor induces the death of neurons in a variety of disorders such as ischaemic stroke, other forms of hypoxic injury, haemorrhagic brain injury, traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease and other dementing diseases. There is thus clear evidence that antagonism of the NMDA receptor will reduce or prevent the neurodegeneration that underlies the disease process in these and related conditions.

There is also evidence to suggest that a well tolerated compound will allow effective symptomatic treatment of the manifestations of the disease process in these disorders as well as reducing the primary underlying neurodegeneration process. Also, it is known that disorders previously described as involving acute neurodegeneration have longer than expected elevations in glutamate release and consequently require longer than expected treatment with NMDA antagonists. There would therefore be a therapeutic avantage for new drugs which are well tolerated and which can therefore be administered chronically.

The published literature contains references to a nimber of compound and classes of compound purported to be useful as NMDA antagonists.

The compound Amantadine and Memantine and related anti-viral agents have been known for many years.

Amantadine

Memantine Patent applications have been filed directe to the use of Memantine in the treatment of Parkinson's Disease in the 1970s and as an NMDA antagonist in 1990 (see EP-A-0392059 and US-A-5061703). Furthermore, International Patent application W094/05275 proposes the use of Amantadine and related compound such as Memantine in the treatment and prevention of non-ischaemic, long term NMDA receptor-mediated neuronal degeneration. An increase in affinity for the NMDA receptor due to substitution of the adamantane ring of Memantine with alkyl groups was noted <BR> <BR> <BR> and published by Kornhuber et al. , Eur. J. Pharmacol., 1991,206,297-300, by Kroemer<BR> <BR> <BR> et al., J. Med. Chem., 1998,41,393-400 and by Parsons et al., Neuropharmacology, 1995,34,1239-1258.

1- (Adamantyl) amidines are disclosed as antivirals in DE-A-2306784, JP-A- 7391049, DD-A-151447 and GB-1478477.1- (Adamantyl) acetamidine is disclosed in JP-A-120683 and GB-1478477.1- (Adamantyl) amidrazones are disclosed as insecticides and acaricides in EP-A-0604798. N-substituted-1- (adamantyl) amidines are disclosed by <BR> <BR> <BR> <BR> May et al. , Arzneim. Forsch., 1978,28,732-735, and the virostatic activities of the compound reporte. N-substituted-1- (adamantyl) amidines as antivirals are disclosed by Skwarski et al. , Acta. Pol. Phare., 1988,45,395-399.

The antiviral activities of adamantane derivatives including 1- <BR> <BR> <BR> <BR> (adamantyl) carbamidine and 1- (adamantyl) acetamidine are reporte by Inamoto et al. , J.

Med. Chem., 1975,18,713-721, where they are compare with Amantadine.

As discussed above, psychotomimetic side-effects are observe during the use of a number of well known NMDA channel blockers and therefore it will be a considerable avantage to identify clinically well-tolerated antagonists where such side effects are minimise. Porter and Greenamyre (J. Neurochem. 1995,64,614-623; incorporated herein by reference) demonstrated that well tolerated and psychotomimetic NMDA receptor channel blockers could be differentiated on the basis of their relative affinities for forebrain and cerebellar receptors irrespective of absolut affinities. Selectivity for cerebellar NMDA receptors over forebrain NMDA receptors is observe for well- tolerated compound. The basis of this observation may be related to different populations of NMDA receptor subtypes in these brain regions.

The use of a nimber of the known NMDA antagonists such as Dizocilpine, PCP, Cerestat and Ketamine gives rise to a number of side effects which render these compound unsuitable for use in treatment. In particular, administration of the compound is associated with perceptual and cognitive disturbances of a kind that resemble naturally-occurring psychotic states.

In addition, the perceptual and cognitive side effects of the compound become more pronounced after the onset of puberty and sexual maturation, and these compound are therefore particularly unsuitable for the treatment of adults. This developmental

change has been demonstrated empirically in both experimental animals and in man, and is paralleled in experimental animals by brain hypermetabolism.

In summary, there is a need for an NMDA antagonist which is well tolerated and does not give rise to the side effects associated with previous clinically investigated NMDA antagonists.

A number of compound have now been found that show affinity for the NMDA receptor and are useful in the treatment of conditions generally associated with abnormalities in glutamatergic transmission such as stroke, traumatic brain injury and neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. It has also been found that the compound have a surprisingly favorable ratio of cortex to cerebellar binding affinity which indicates that these compound should be well tolerated in vivo.

According to the present invention there is provided use of a compound of the formula (1): wherein X is an alkylene chain comprising 0,1,2,3 or 4 carbon atoms; Rl, RZ and R3 are independently selected from hydrogen, alkyl and aryl; R4, R5 and R6 are independently selected from hydrogen, alkyl, aryl, halogen and alkoxy; and prodrugs thereof and pharmaceutically acceptable salts thereof; in the manufacture of a medicament for use in the treatment of a condition generally associated with abnormalities in glutamatergic transmission.

As used herein, the term"alkyl"means a branche or unbranched, cyclic or acyclic, saturated or unsaturated (e. g. alkenyl or alkynyl) hydrocarbyl radical. Where <BR> <BR> <BR> <BR> cyclic, the alkyl group is preferably C3 to Cl2, more preferably C5 to Ciao, more preferably<BR> <BR> <BR> <BR> <BR> <BR> <BR> C5 to C7-Where acyclic, the alkyl group is preferably Cl to Clo, more preferably Cz to C6, more preferably methyl, ethyl or propyl, more preferably methyl or ethyl.

As used herein, the term"aryl"means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteratom, such as pyridyl, pyrrolyl, furanyl and thiophenyl. Preferably, the aryl group comprises phenyl.

The alkyl and aryl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include:- carbon containing groups such as alkyl, aryl, arylalkyl; (e. g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl) halogen atoms and halogen containing groups such as haloalkyl (e. g. trifluoromethyl); oxygen containing groups such as alcools (e. g. hydroxy, hydroxyalkyl, (aryl) (hydroxy) alkyl), ethers (e. g. alkoxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e. g. carboxaldehyde), ketones (e. g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl) acids (e. g. carboxy, carboxyalkyl), acid derivatives such as esters (e. g. alkoxycarbonyl, alkoxycarbonylalkyl, alkycarbonylyoxy, alkycarbonylyoxyalkyl) and amides

(e. g. aminocarbonyl, mono-or dialkylaminocarbonyl, aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl, arylaminocarbonyl); nitrogen containing groups such as amines (e. g. amino, mono-or dialkylamino, aminoalkyl, mono-or dialkylaminoalkyl), azides, nitriles (e. g. cyano, cyanoalkyl), nitro; sulphur containing groups such as thiols, thioethers, suphoxides, and sulphones (e. g. alkylthio, alkylsulfinyl, alkylsufonyl, alkylthioalkyl, alkylsulfinylalkyl, arylsulfinyl,alkylsulfonylalkyl,arylthio, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl) and heterocyclic groups containing one or more, preferably one, heteroatom, (e. g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl,

chromenyl, chromanyl, isochromanyl and carbolinyl).

As used herein, the term"alkoxy"means alkyl-O-and"alkoyl"means alkyl-CO-.

As used herein, the term"halogen"means a fluorine, chlorine, bromine or iodine radical, preferably a bromine or chlorine radical.

As used herein the term"conditions generally associated with abnormalities in glutamatergic transmission"primarily inclues ischaemic stroke, haemorrhagic stroke, subarrachnoid haemorrhage, subdural haematoma, coronary artery bypass surgery, neurosurgery, traumatic brain injury, traumatic spinal injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Lewy body disease, senile dementia, spongiform encephalopathies, prion-protein induced neurotoxicity, peri-natal asphyxia, demyelinating disease, multiinfarct dementia, dementia pugilans, drug dependence, alcohol withdrawal, opiate withdrawal, motor neurone disease, multiple sclerosis, acute and chronic pain including neuropathic pain, cancer pain, trigeminal neuralgia, migraine, primary and secondary-hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain, HIV pain and diabetic neuropathy. In addition, the term also inclues the following conditions: epilepsy, multiple system atrophy, progressive supra- nuclear palsy, Friedrich's ataxia, autism, fragile X syndrome, tuberous sclerosis, attention deficit disorder, olivio-ponto-cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, peripheral neuropathy, myelopathy, ischaemic retinopathy, glaucoma, cardiac arrest, encephalitis, depression, bi-polar disorder, schizophrenia, psychosis, behaviour disorders, impulse control disorders, pre-eclampsia, neuroleptic alignant syndrome, chronic fatigue syndrome, anorexia nervosa, anxiety disorders, generalised anxiety disorder, panic disorder, phobias, fresh water drowning and decompression.

As used herein, the term"treatment"also inclues prophylactic treatment.

As used herein, the term"pharmaceutically acceptable salt"means any pharmaccutically acceptable salt of the compound of formula (1). Salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.

Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic, ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.

The compound of formula (1) may exist in a number of diastereomeric and/or enantiomeric forms. Reference in the present specification to"a compound of formula (1)"is a reference to all stereoisomeric forms of the compound and inclues a reference to the unseparated stereoisomers in a mixture, racemic or non-racemic, and to each stereoisomer in its pure form.

The compound of the present invention are active as NMDA antagonists and are well tolerated in that side effects are minimise. Experimental data are shown in Table 1.

In the compound of formula (1), preferably X is an alkylene chain comprising 0, 1 or 2 carbon atoms, more preferably 0 carbon atoms, in the chain.

In one embodiment of the invention, in the compound of formula (1), where X is an alkylene chain comprising 1,2,3 or 4 carbon atoms, one or more of the carbon atom (s) in the chain X may be independently substituted by substituent group (s) selected from alkyl and aryl. Where substituted, a carbon atom may have one or two substituents, preferably one. Preferred substituent groups are selected from methyl, ethyl, phenyl and benzyl, preferably ethyl and benzyl. Where X is substituted, it is preferred that only one carbon atom in the chain is substituted.

In an alternative embodiment of the invention, in the compound of formula (1), X is unsubstituted and has the formula (CHZ)"where n = 0 to 4, preferably n = 0,1 or 2 and more preferably n = 0.

In the compound of formula (1), preferably Rl and RZ are hydrogen and R3 is selected from hydrogen, alkyl and aryl. In a preferred embodiment, Rl, R2 and R3 are hydrogen.

In the compound of formula (1), preferably at least one of R4, W and R6 is alkyl, aryl, halogen or alkoxy. Preferably R4 is selected from hydrogen, alkyl and halogen, <BR> <BR> <BR> more preferably alkyl and more preferably methyl. Preferably R5 is selected from hydrogen and alkyl, preferably hydrogen and methyl. Preferably R6 is selected from hydrogen and alkyl, preferably hydrogen and methyl.

In a preferred embodiment, the compound of formula (1) is a compound where X <BR> <BR> <BR> has 1 carbon atom (i. e. n = 1) and is unsubstituted; Rl, R2 and R3 are hydrogen; R4 and<BR> <BR> <BR> <BR> <BR> <BR> Rus are methyl; and R6 is hydrogen.

In a further preferred embodiment, the compound of formula (1) is a compound where X has one carbon atom (i. e. n = 1) and is substituted by an ethyl or benzyl group; and R1, R2, R3, R4, R5 and R6 are hydrogen.

In a particularly preferred embodiment, the compound of formula (1) is a <BR> <BR> <BR> compound of formula (1) where X has 0 carbon atoms (i. e. n = 0); Rl, RZ and R3 are<BR> <BR> <BR> <BR> <BR> <BR> hydrogen; R4 and R5 are ;CH3 and R6 is hydrogen.

In a further particularly preferred embodiment, the compound of formula (1) is a <BR> <BR> <BR> compound where X has 0 carbon atoms (i. e., n = 0); Rl, R2 and R3 are hydrogen; W is<BR> <BR> <BR> <BR> <BR> <BR> methyl; and R5 = R6 = hydrogen or methyl.

The present invention further provides a method of treatment of conditions generally associated with abnormalities in glutamatergic transmission comprising

administering to a patient an effective dose of a compound of formula (1) as defined above.

The present invention also provides a compound per se of the formula (1) as defined above wherein at least one of R4, R5 and R6 is alkyl, aryl, halogen or alkoxy, with the proviso that if Rl, R2 and R3 are hydrogen and R4, R5 and R6 are independently selected from hydrogen and Cl 4 alkyl, then either X is an alkylene chain of 2-4 carbon atoms, substituted or unsubstituted, as defined above, or X is an alkylene chain of 1 carbon atom substituted with one or two, preferably one, substituent group (s) independently selected from alkyl and aryl, and prodrugs and pharmaceutically acceptable salts thereof.

The present invention also provides a compound per se of the formula (1) as defined above wherein R4, Rs and R6 are hydrogen and either X is an alkylene chain of 2-4 carbon atoms, substituted or unsubstituted, as defined above, or X is an alkylene chain of 1 carbon atom substituted with one or two, preferably one, substituent group (s) independently selected from alkyl and aryl, or X is a CHEZ. group, with the proviso that where X is a CH2 group then at least one of Rl, R2 and R3 are selected from alkyl and aryl, and prodrugs and pharmaceutically acceptable salts thereof.

The present invention also provides compound per se of formulae (2), (3), (4) and (5):

and prodrugs and pharmaceutically acceptable salts thereof.

The present invention also provides, for use in therapy: (i) a compound of the formula (1) as defined above wherein at least one of R4, R5 and R6 is alkyl, aryl, halogen or alkoxy, with the proviso that if Rl, R2 and R3 are hydrogen and R, R 5 and R6 are independently selected from hydrogen and Cl 4 alkyl, then either X is an alkylene chain of 2-4 carbon atoms, substituted or unsubstituted, as defined above, or X is an alkylene chain of 1 carbon atom substituted with one or two, preferably one, substituent groups independently selected from alkyl and aryl; (ii) a compound of the formula (1) as defined above wherein R4, R5 and R6 are hydrogen and either X is an alkylene chain of 2-4 carbon atoms, substituted or unsubstituted, as defined above, or X is an alkylene chain of 1 carbon atom substituted with one or two, preferably one, substituent groups independently selected from alkyl and aryl, or X is a

CH2 group, with the proviso that where X is a CH2 group then at least one of Rl, R2 and R3 are selected from alkyl and aryl; and (iii) a compound of formula (2), (3), (4) or (5) as defined above, and prodrugs and pharmaceutically acceptable salts thereof.

The present invention also provides a pharmaceutical composition comprising: (i) a compound of the formula (1) as defined above wherein at least one of R4, R5 and R6 is alkyl, aryl, halogen or alkoxy, with the proviso that if Rl, R2 and R3 are hydrogen and R4, Rs and R6 are independently selected from hydrogen and Cl 4 alkyl, then either X is an alkylene chain of 2-4 carbon atoms, substituted or unsubstituted, as defined above, or X is an alkylene chain of 1 carbon atom substituted with one or two, preferably one, substituent group independently selected from alkyl and aryl; or (ii) a compound of the formula (1) as defined above wherein R4, R'and R6 are hydrogen and either X is an alkylene chain of 2-4 carbon atoms, substituted or unsubstituted, as defined above, or X is an alkylene chain of 1 carbon atom substituted with one or two, preferably one, substituent groups independently selected from alkyl and aryl, or X is a CH2 group, with the proviso that where X is a CH2 group then at least one of Rl, R2 and R3 are selected from alkyl and aryl; or (iii) a compound of formula (2), (3), (4) or (5) as defined above, and prodrugs and pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable excipient.

According to a further aspect of the present invention there is provided a method of preparing the compound of the present invention. Compound of formula (1) may be prepared by conventional synthetic routes; see for example DD-A-151447, US-A- 5061703, DE-A-2306784, GB-1478477, Skwarski et al., Acta. Polon. Pharm., (1988), 45, 395-399 and May et al., Arzneim. Forsch., (1978), 28,732-735, the disclosures of which are incorporated herein by reference.

The following rection schemes describe examples of synthetic routes for the preparation of compound falling within formula (1). The rection schemes are included for the purpose of exemplification only and are not intended to be limiting to the invention.

Compound of formula (1) may be synthesised by conventional synthetic methods as illustrated in Scheme 1.

Scheme 1 Amidines of formula 4 may be synthesised from nitriles of formula 3 by conventional methods, for example by treatment with an amine in the presence of trimethyl aluminium in a refluxing solvent such as toluene for several days, or alternatively by treatment with HCl in dry methanol at 0°C for several days followed by treatment with NH3 at room temperature. Nitriles of formula 3 may be synthesised from carboxylic acids of formula 2 by conventional methods, for example by treatment with methanesulphonyl chloride in the presence of pyridine, followed by treatment with NH3,

followed by treatment with methanesulphonyl chloride in the presence of pyridine.

Carboxylic acids of formula 2 are either commercially available or may be synthesised <BR> <BR> <BR> <BR> by conventional methods such as those published in Stetter et al. , Chem. Ber., 1962,95,<BR> <BR> <BR> <BR> <BR> <BR> 667-672, by Koch et al. , Chem. Ber., 1963,96,213-219, by Stepanov et al. , Zh. Obstrich.<BR> <BR> <BR> <BR> <BR> <BR> <P>Khim., 1964,34,579-584, by Stepanov et al. , Zh. Org. Khim., 1965,1,280-283 and by<BR> <BR> <BR> <BR> <BR> <BR> Stepanov et al. , Zh. Org. Khim., 1966,2,1612-1615.

An alternative route for the preparation of compound of formula (1) where X is CR7R8 wherein R7 and R8 are independently hydrogen or alkyl and wherein R, R2, R3, R4, Rs and R6 are as defined in formula (1), also involving conventional methods, is illustrated in Scheme 2.

Scheme 2 Amidines of formula 7 may be prepared from nitriles of formula 6 as described above. Nitriles of formula 6 may be prepared from nitriles of formula 5 by alkylation or dialkylation, for example by treatment with a base such as LDA followed by treatment with an alkyl halide. Further treatment with a base followed by a second alkyl halide would give the dialkylated nitrile.

An alternative route for the preparation of compound of formula (1) where X is CHR9CH2 or CH, CHR" wherein R9 and Rl° are independently alkyl or aryl and wherein RI, RZ, R3, R4, RS and R6 are as defined above, also involving conventional methods, is illustrated in Scheme 3.

Scheme 3

Amidines of formula 11 may be prepared from nitriles of formula 10 as described above. Nitriles of formula 10 may be prepared by reduction of unsaturated nitriles of formula 9, for example by hydrogenation in the presence of a transition metal catalyst such as palladium on carbon. Nitriles of formula 9 may be prepared from ketones or aldehydes of formula 8 by conventional methods such as the Horner-Emmons olefination rection using an appropriately substituted phosphonate in the presence of a base such as sodium hydrie. Ketones or aldehydes of formula 8 are commercially available or may be synthesised by conventional methods.

In addition, compound of formula (1) where X is an alkylene chain of 3 or 4 carbon atoms may be synthesised by conventional methods as illustrated in Scheme 4. In Scheme 4RlR2R3 R4, Rs and R6 are as defined above and R9RI°Rll and Ruz are independently selected from hydrogen, alkyl and aryl.

Scheme 4

Amidines of formula 16 and 17 may be synthesised from nitriles of formula 15 and 12 respectively by the methods described in Scheme 1. Nitriles of formula 15 may be synthesised from nitriles of formula 14 by methods described in Scheme 3 or alternatively from ketones of formula 13 by reduction to the alcohol followed by tosylation or bromination, followed by cyanide displacement. Nitriles of formula 14 may be synthesised from ketones of formula 11 by methods described in Scheme 3. Ketones of formula 13 may be synthesised from nitriles of formula 12 by the addition of a Grisard reagent followed by hydrolytic work-up. Nitriles of formula 12 may be prepared from ketones of formula 11 by the reduction, tosylation/bromination and cyanide displacement sequence described above. Ketones of formula 11 may be prepared from nitriles of formula 10 by Grignard rections as described above.

Additional substituents may be introduced into the alkylene chain X by methods analagous to those described in the above schemes and by other conventional synthetic methods.

The compound of formula (1) may be administered in a form suitable for oral use, for example a tablet, pellet, capsule, aqueous or oily solution, suspension or mulsion; for topical use including transmucosal and transdermal use, for example a cream, ointment, gel, aqueous or oil solution or suspension, salve, patch or plaster; for nasal use, for a example a snuff, nasal spray, nasal powder or nasal drops; for vaginal or rectal use, for example a suppository or pessary; for administration by inhalation, for example a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; for ocular use, for example a sterile aqueous solution or sterile ointment; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oil solution or suspension or mulsion, or depot injection formulation. In general the above compositions may be prepared in a conventional manner using conventional excipients, using standard techniques, including controlled release technologies, such as gelatin, lipid, gel depot, liposome and microcapsule based systems well known to those skilled in the art of pharmacy.

For oral administration, the compound of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.

Tablets or pellets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, calcium hydrogen phosphate, cellulose derivatives and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch, gelatin and polyvinyl-pyrrolidone derivatives, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be formulated or coated with a material such as glyceryl monostearate or

glyceryl distearate or polymethacrylate polymers, cellulose derivatives or other pharmaceutically acceptable polymer, to delay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compound of the invention will generally be provided in sterile aqueous solutions or suspensions or mulsions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

Transdermal formulations include membrane permeation systems, multi-laminate adhesive dispersion systems and matrix dispersion systems. Transdermal delivery also inclues the use of electrically aided transport and skin penetration enhancers and needle- free injection devices.

The preferred route of administration will be as an intravenous infusion, preferably over a period of up to seven days, or as an oral formulation, or as an intramuscular injection via a strette or as a subcutaneous injection.

It will be appreciated that the dosage levels used may vary over quite a wide range depending upon the compound used, the severity of the condition exhibited by the patient and the patient's body weight. However, without commitment to a rigid definition of dosages it may be stated that a daily dosage of the active constituent (estimated as the free base) is lOOgg to 800mg. More particularly, the preferred compound may be administered at a preferred dose of 50-800mg/day, in single or divided doses.

The invention will now be described in detail. It will be appreciated that the invention is described by way of example only and modification of detail may be made without departing from the scope of the invention. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>EXPERIMENTAL<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> I Svnthesis Example 1 3,5-Dimethyl-1-adamantanecarboximidamide hydrochloride 3,5-Dimethyl-1-adamantanecarbonitrile A solution of 3, 5-dimethyl-1-adamantanecarboxylic acid (2.51 g, 12.1 mmol) in dry pyridine (40 mL) at 0°C was treated dropwise with methanesulphonyl chloride (1.4 g, 12.2 mmol), stirred for 2 h, saturated with ammonia gas, stirred for 5 min and the excess ammonia removed in vacuo. The resulting suspension at 0°C was treated with methanesulphonyl chloride (11.8 g, 102 mmol), stirred overnight at room temperature, poured into cold 1-M HCl (200 mL) and extracted with EtOAc (3 x 40 mol). The organic phase was washed with dilute HCl (50 mL), water (50 mL), dried (MgS04), concentrated in vacuo and the residue purifie by chromatography [Si02; CH2Cl2] to give the product (1.97 g, 86 %) as a pale brown oil: IR #max (liquid film)/cm-1 2922, 2849,2235,1455, <BR> <BR> <BR> <BR> 1359 and 1098; NMR sH (400 MHz, CDCl3) 0.87 (6H, s), 1.19 (2H, s), 1.3-1.45 (4H, m), 1.55-1.75 (4H, ion), 1.8-1.9 (2H, m) and 2.1-2.15 (1H, m).

3,5-Dimethyl-1-adamantanecarboximidamide hydrochloride A solution of 3, 5-dimethyl-1-adamantanecarbonitrile (1.95 g, 10.3 mmol) in MeOH (30 mL) at 0°C was saturated with HCl gas over 30 min, left at 0°C for 5 days, concentrated in vacuo, the residue triturated with EtOAc and filtered to give the intermediate imidate hydrochloride salt (1.16g, 44 %) as a hygroscopic solid. The solid (302 mg, 1.17 mmol) in MeOH (20 mL) at 0°C was saturated with anunonia gas, left at room temperature for 4 days, concentrated to a small volume in vacuo, treated with EtOAc and filtered to give <BR> <BR> <BR> the title compound (240 mg, 85 %) as a white crystalline solid: mp 297-229°C ; IR vt"aX

(Nujol)/cm-1 3166, 1673,1508,1087 and 729; NMR 5H (400 MHz, DMSO-d6) 0.85 (6H, s), 1.20-1.50 (2H, m), 1.30-1.40 (4H, m), 1.40-1.60 (4H, m), 1.69 (2H, m), 2.12 (2H, m), 8.55 (2H, br s) and 8.90 (2H, br s); Anal. Calcd for C13H23N2CI-0. 1 H20: C, 63.84; H, 9.56; N, 11.45. Found: C, 63.73; H, 9. 34; N, 11.46.

Example 2 3-Chloro-l-adamantanecarboximidamide hydrochloride 3-Chloro-l-adamantanecarbonitrile This was prepared from 3-chloro-1-adamantanecarboxylic acid by the method of example 1 and the product isolated (2.12g, 94 %) as a pale brown solid: mp 156-157°C ; <BR> <BR> <BR> IR #max (Nujol)/cm-1 2249, 2230, 1248,1124,972 and 734; NMR aH (400 MHz, CDC13) 1.64-1.73 (2H, m), 1.96-2.04 (4H, m), 2.07-2.16 (4H, m), 2. 25-2.30 (2H, m) and 2.38 (2H, s); Anal. Calcd for CIIH14NCI: C, 67.52; H, 7.21; N, 7.15. Found: C, 67.52; H, 7.18; N, 6.94.

3-Chloro-1-adamantanecarboximidamidehydrochloride This was prepared from 3-chloro-1-adamantanecarbonitrile by the method of example 1 and the title compound isolated (272 mg, 96 %) as a white crystalline solid: mp 215-216 °C ; IR #max (Nujol)/cm-1 3455, 3376,3306,3148,1687,1667,1082,837,733 and 701; <BR> <BR> <BR> <BR> NMR aH (400 MHz, DMSO-d6) 1.55-1.65 (2H, m), 1.80-1.90 (4H, m), 2.05-2.15 (4H, m), 2.25 (2H, s), 2.28 (2H, s), 8.70 (2H, s) and 9.04 (2H, s); Anal. Calcd for C11H18N2Cl2#H2O#0.1 NH4Cl : C, 48.48; H, 7.54; N, 10.79. Found: C, 48.81; H, 7.63; N, 10.86.

Example 3 3-Bromo-1-adamantanecarboximidamidehydrochloride This was prepared from 3-bromo-1-adamantanecarbonitrile by the method of example 1 and the title compound isolated (276 mg, 97 %) as a white crystalline solid: mp 221-223 °C ; IR vma, (Nujol)/cm~ 3453,3373,3307,3152,1687,1667,1081,825,722,699 and 679; NMR 8H (400 MHz, DMSO-d6) 1.60-1.70 (2H, m), 1.85-1.95 (4H, m), 2.21 (2H,

s), 2.25-2.35 (4H, m), 2.50 (2H, s) and 8.8 (4H, br s); Anal. Calcd for C11H18N2BrCl# H20: C, 42.39; H, 6.47; N, 8.99. Found: C, 42.17; H, 6.48; N, 9.08.

Example 4 3-Ethyl-1-adamantanecarboximidamide hydrochloride This was prepared from 3-ethyl-1-adamantanecarbonitrile by the method of example 1 and the title compound isolated (1.74 g, 94 %) as a white crystalline solid: mp 210-212 <BR> <BR> <BR> °C; IR #max (Nujol)/cm-1 3266, 3070,1665,1089 and 734; NMR aH (400 MHz, DMSO- d6) 0.79 (3H, t, J7.75 Hz), 1.1-1.2 (2H, m), 1.35-1.45 (4H, m), 1.5-1.65 (4H, m), 1.7 -1.85 (2H, m), 2.09 (2H, s), 8.56 (2H, br s) and 8.92 (2H, br s); Anal. Calcd for C13H23N2CI: C, 64.31; H, 9.55; N, 11.53. Found: C, 64.05; H, 9.95; N, 11.49.

Example 5 3,5-Dimethyl-1-adamantaneacetimidamidehydrochloride 3,5-Dimethyl-l-adamantaneacetonitrile This was prepared from 3,5-dimethyl-1-adamantaneacetic acid (Bott and Hellman, Angew. Chem. Int. Ed. Engl., 1966,5,870, the disclosure of which is incorporated herein <BR> <BR> <BR> <BR> by reference) by the method of example 1 and the product isolated (833 mg, 88 %) as a pale brown oil: IR #max (liquid film)/cm~ 2900,2843,2244,1455,1360 and 1345; NMR <BR> <BR> <BR> <BR> 6H (400 MHz, CDCl3) 0.84 (6H, s), 1.1-1.3 (6H, m), 1. 32-1. 35 (2H, m), 1.44-1.47 (2H, m), 2.12 (2H, s) and 2.05-2.15 (1H, m).

3, 5-Dimethyl-1-adamantaneacetimidamide hydrochloride This was prepared from 3, 5-dimethyl-1-adamantaneacetonitrile by the method of example 1 and the title compound isolated (778 mg, 100 %) as a white crystalline solid: <BR> <BR> <BR> mp 252-253°C ; IR #max (Nujol)/cm-1 3384, 3076,1691 and 722; NMR sH (400 MHz, DMSO-d6) 0.81 (6H, s), 1.0-1.25 (6H, m), 1.25-1.35 (4H, m), 1.38 (2H, s), 2.04 (1H, m), 2.17 (2H, s) and 8.76 (4H, br s); Anal. Calcd for C14H25N2Cl#0.9 H2O : C, 61.59; H, 9.89; N, 10.26. Found: C, 61.69; H, 10.31; N, 10.19.

Example 6 N-Allyl-3,5-dimethyl-1-adamantanecarboximidamidehydrochlorid e This was prepared from 3, 5-dimethyl-1-adamantanecarbonitrile by the method of example 1 using allylamine (3 eq) instead of ammonia. The title compound was isolated (46 mg, 42 %) as a white crystalline solid: mp 222-224°C ; IR #max (Nujol)/cm-1 3039, <BR> <BR> <BR> <BR> 1671,1614,993,932,810 and 722; NMR 6H (400 MHz, DMSO-d6) 0.85 (6H, s), 1.16- 1.19 (2H, m), 1.3-1. 4 (4H, m), 1.48-1.6 (4H, m), 1.75 (2H, m), 2.14 (1H, m), 3.92 (2H, m), 5.10-5.20 (2H, m), 5.75-5.85 (1H, m), 8.7 (2H, br s) and 9.0 (1H, br s); Anal.

Calcd for Cl6H27N2Cl 0.2 H20: C, 67.09; H, 9.64; N, 9.78. Found: C, 67.09; H, 9.56; N, 9.53.

Example 7 N-Allyl-1-adamantanecarboeimidamide hydrochloride This was prepared from 1-adamantanecarbonitrile by the method of example 1 using allylamine (3 eq) instead of ammonia. The title compound was isolated (298 mg, 90 %) as a white crystalline solid: mp 252-254°C ; IR #max (Nujol)/cm-1 3185, 3031,1678, <BR> <BR> <BR> <BR> 1613,1257,799,751 and 717; NMR 5H (400 MHz, DMSO-d6) 1.65-1.70 (6H, m), 1.9- 2.0 (6H, m), 2.04 (3H, s), 3.95 (2H, m), 5.1-5.2 (2H, m), 5.75-5.85 (1H, m), 8.71 (1H, s), 8.79 (1H, s) and 9.15 (1H, s); Anal. Calcd for Cl4H23N2Cl: C, 65.99; H, 9.10; N, 10.99. Found: C, 65.92; H, 9.04; N, 11.05.

Example 8 N-Ethyl-1-adamantanecarboximidamidehydrochloride This was prepared from 1-adamantanecarbonitrile by the method of example 1 using 2-M ethylamine in MeOH (3 eq) in place of ammonia and the title compound isolated (175 mg, 55 %) as a white crystalline solid: mp 315°C (dec); IR #max (Nujol)/cm-1 3191, 3030, <BR> <BR> <BR> <BR> 1682,1616,1354, 810 and 766; NMR aH (400 MHz, DMSO-d6) 1.10 (3H, t, J 7.0 Hz), 1.6-1.7 (6H, m), 1.85-1.90 (6H, m), 2.0-2.05 (3H, m), 3. 30 (2H, pent, J7.0 Hz), 8.67 (1H, s), 8.71 (1H, s) and 8.86 (1H, s); Anal. Calcd for C13H23NZCl: C, 64.31; H, 9.55; N, 11.54. Found: C, 64.27; H, 9.56; N, 11.54.

Example 9 N-Benzyl-1-adamantanecarboximidamide hydrochloride This was prepared from 1-adamantanecarbonitrile by the method of example 1 using benzylamine (1.1 eq) in place of ammonia and the title compound isolated (357 mg, 90 %) as a white crystalline solid: mp 242-244 °C; 1R v=" (Nujol)/cm~l 3049,1677,1605, 1240,759,728 and 703; NMR 8H (400 MHz, DMSO-d6) 1.65-1.70 (6H, m), 1.9-2.0 (6H, m), 2.05 (3H, s), 4.58 (2H, s), 7.3-7.4 (5H, m), 8.80 (1H, s), 8.85 (1H, s) and 9. 55 (1H, s); Anal. Calcd for Cz8H25N2Cl: C, 70.92; H, 8.27; N, 9.18. Found: C, 70.62; H, 8.21; N, 9.18.

Example 10 N-(2-Dimethylaminoethyl)-1-adamantanecarboximidamidedihydroc hloride This was prepared from 1-adamantanecarbonitrile by the method of example 1 using N, N-dimethylethylenediamine (3 eq) in place of ammonia and the title compound isolated (42 mg, 10 %) as a white crystalline solid: mp 293°C (dec); IR #max (Nujol)/cm-1 <BR> <BR> <BR> 3192,2581,2469,1697,1605 and 798; NMR aH (400 MHz, DMSO-d6) 1.65-1.75 (6H, ion), 1.94 (6H, s), 2.04 (3H, s), 2.81 (6H, s), 3.27 (2H, m), 3.72 (2H, m), 8.98 (1H, s), 9.04 (1H, s), 9.13 (1H, s) and 10 86 (1H, s); Anal. Calcd for C15H29N3CI2. 0.25 H20: C, 55.12; H, 9.10; N, 12.86. Found: C, 55.23; H, 9.00; N, 12.89.

Example 11 3- (3, 5-Dimethyl-1-adamantyl) propanimidamide hydrochloride 3-(3,5-Dimethyl-1-adamantyl)propionitrile A solution of 1-bromo-3, 5-dimethyladamantane (1.0 g, 4.11 mmol), acrylonitrile (436 mg, 8.22 mmol) and 1,1'-azobis (cyclohexanecarbonitrile) (50 mg, 0.21 mmol) in dry toluene (12 mL) was treated with tri-n-butyltin hydride (1.44 g, 4.93 mmol) at room temperature, refluxed for 3.5 h, cooled, diluted with ether (30 mol), washed with 0.2-M NH4OH (30 mL), water (10 mL), dried (MgS04) and concentrated in vacuo. The residue <BR> <BR> <BR> was purifie by chromatography [sio2, CH2Cl2-hexane (0: 100 to 100: 0)] to give the<BR> <BR> <BR> <BR> <BR> product (771 mg, 86 %) as a colourless oil: IR #max (liquid film)/cm-1 2899, 2841,2247, 1545 and 1359; NMR 8H (400 MHz, CDCl3) 0.81 (6H, s), 1.0-1.2 (6H, ion), 1. 25 - 1.35 (6H, ion), 1.53 (2H, t, J4.2 Hz), 2.05-2.10 (1H, m) and 2.27 (2H, tJ4.2 Hz).

3-(3,5-Dimethyl-1-adamantyl)propanimidamidehydrochloride This was prepared from 3- (3, 5-dimethyl-1-adamantyl) propionitrile by the method of example 1 and the title compound isolated (609 mg, 86 %) as a white crystalline solid: <BR> <BR> <BR> mp 246-248°C ; IR #max (Nujol)/cm-1 3076, 1681,789 and 749; NMR 6H (400 MHz, DMSO-d6) 0.80 (6H, s), 1.08 (6H, q, J 12.5 Hz), 1.28 (6H, d J 2.6 Hz), 1.39 (2H, m), 2.02 (1H, m), 2.31 (2H, ion), 8.65 (2H, br s) and 8.99 (2H, br s); Anal. Calcd for C15H25N2Cl#0.2 NH4Cl : C, 63.99; H, 9.95; N, 10.95. Found: C, 64.15; H, 9.98; N, 10.87.

Example 12 3-Methyl-1-adamantanecarboximidamidehydrochloride 3-Methyl-l-adamantanecarbonitrile This was prepared from 3-methyl-1-adamantanecarboxylic acid by the method of example 1 and the product (1.81 g, 80 %) isolated as a pale brown waxy solid: IR V", ax <BR> <BR> <BR> (Nujol)/cm-1 2923, 2853,2233,1456,1377,1360,1343,1161 and 1111; NMR 5H (400 MHz, CDCl3) 0.85 (3H, s), 1.45 (4H, m), 1.63 (2H, m), 1.74 (2H, s), 1.94 (4H, m) and 2.07 (2H, ion).

3-Methyl-l-adamantanecarboximidamide hydrochloride This was prepared from 3-methyl-1-adamantanecarbonitrile by the method of example 1 and the title compound (1.26 g, 95 %) isolated as a white crystalline solid: mp 255- 257°C ; IR vmax (Nujol)/cm 3222,3084,2923,2853,1674,1502,1456,1376,1087 <BR> <BR> <BR> <BR> and 737; NMR 8H (400 MHz, DMSO-d6) 0.83 (3H, s), 1.42 (4H, m), 1.58 (4H, m), 1.77 (4H, m), 2.07 (2H, m), 8.61 (2H, br s) and 8.99 (2H, br s); NMR 6c (100 MHz, DMSO-d6) 28.1,30.2,30.8,34.9,37.5,42.7,44.6 and 177.0.

Example 13 3,5,7-Trimethyl-1-adamantanecarboximidamide hydrochloride 3,5, 7-Trimethyl-l-adamantanecarbonitrile This was prepared from 3,5, 7-trimethyl-1-adamantanecarboxylic acid by the method of example 1 and the product (2.01 g, 88 %) isolated as a waxy solid: IR Vmax <BR> <BR> <BR> (Nujol)/cm~l 2923,2864,2230, 1456,1377,1358,1350,1257,1095 and 912; NMR sH<BR> <BR> <BR> <BR> <BR> <BR> (400 MHz, CDCl3) 0.90 (9H, s), 1.12 (6H, m) and 1.60 (6H, s).

3,5,7-Trimethyl-1-adamantanecarboximidamidehydrochloride This was prepared ftom 3,5, 7-trimethyl-1-adamantanecarbonitrile by the method of example 1 and the title compound (0.98 g, 98 %) isolated as a white crystalline solid:

mp 325 °C ; IR #max (Nujol)/cm-1 3266, 3094,2923,2854,1666,1517,1454,1376,<BR> <BR> <BR> <BR> <BR> <BR> 1365,1113,1098 and 741; NMR 6H (400 MHz, DMSO-d6) 0.86 (9H, s), 1.09 (6H, ion), 1.44 (6H, s), 8.59 (2H, br s) and 8.99 (2H, br s); NMR 6c (100 MHz, DMSO-d6) 30.0, 31.8,40.9,43.5,49.2 and 176.7.

Example 14 3-(4-Nitrophenyl)-1-adamantanecarboximidamidehydrochloride 3-(4-Nitrophenyl)-1-adamantanecarbonitrile This was prepared from 3-(4-nitrophenyl)-1-adamantanecarboxylic acid by the method of example 1 and the product (0.92 g, 93 %) isolated as a pale brown solid: IR #max <BR> <BR> <BR> <BR> (Nujol)/cm-1 2923, 2854,2235,1594,1516,1458,1377,1353,1111 and 858; NMR aH<BR> <BR> <BR> <BR> <BR> <BR> (400 MHz, CDCl3) 1.79 (2H, ion), 1.94 (4H, ion), 2.11 (4H, ion), 2.21 (2H, s), 2.30 (2H, ion), 7.49 (2H, m) and 8.20 (2H, ion).

3-(4-Nitrophenyl)-1-adamantanecarboximidamidehydrochlorid e This was prepared from 3- (4-nitrophenyl)-1-adamantanecarbonitrile by the method of example 1 and the title compound (0.22 g, 77 %) isolated as a white crystalline solid: mp 256 - 259 °C ; IR #max (Nujol)/cm-1 3448, 3365,3314,3160,3074,2923,2854, <BR> <BR> <BR> <BR> 1686,1664,1608,1596,1512,1455,1377,1351,741 and 697; NMR sH (400 MHz, DMSO-d6) 1.72 (2H, ion), 1.93 (8H, ion), 2.09 (2H, s), 2.25 (2H, m), 7.75 (2H, m), 8.21 (2H, m), 8.73 (2H, br s) and 8.93 (2H, br s).

Example 15 2- (I-Adamantyl) butanimidamide hydrochloride 2- (I-Adamantyl)butanenitrile A solution of diisopropylamine (0.45 mL, 3.2 mmol) in dry THF (15 mL) at -78 °C was treated with n-BuLi (1.6-M, 2 mL, 3.2 mmol), stirred at -78°C for 15 min, treated with a solution of 2-(1-adamantyl) acetonitrile (0.5 g, 2.9 mmol) in dry THF (5 mL) and stirred at -78°C for 1 h. Ethyl iodide (0.26 mL, 3.2 mmol) was added

dropwise, the solution stirred at -78 °C for 2 h, allowed to warm to room temperature, treated with NH4Cl solution (20 mL), extracted with EtOAc (3 x 10 mL), the extracts washed with brine (10 mL), dried (MgS04) and concentrated in vacuo to give the product (0.56 g, 97 %) as a pale brown solid: mp 53 - 54°C ; IR vm (Nujol)/cm-1 <BR> <BR> <BR> 2914,2231,1455,1378,1366,1346,1317,1091 and 979;. NMR 6H (400 MHz, CDCl3) 1.11 (3H, t, J 7.4 Hz), 1.49 (1H, m), 1.74-1.64 (13H, m) and 2.06 (4H, m); Anal. Calcd for Cz4H21N 0.1 H20: C, 81.97; H, 10.42; N, 6.83. Found: C, 81.92; H, 10.68; N, 6.74.

2-(1-Adamantyl)butanimidamidehydrochloride A suspension of NH4Cl (1.38 g, 26 mmol) in dry toluene (8 mL) at 0 °C was treated dropwise with 2-M trimethylaluminium in toluene (13 mL, 26 mmol), allowed to warm to room temperature and stirred for 2 h. This solution was added to a solution of 2- (l-adamantyl) butanenitrile (0.44 g, 2.2 mmol) in dry toluene (10 mL) and the resulting solution refluxed for 4 days, cooled to room temperature and poured into a <BR> <BR> <BR> slurry of sio2 (5 g) and CHOC13 (10 mL). The slurry was filtered, the filtrate treated with Na2SO4, concentrated in vacuo and the residue loaded on to the top of a silica <BR> <BR> <BR> column and purifie by chromatography [Si02; EtOAc-MeOH (9: 1 to 4: 1)] to give the title compound (0.38 g, 68 %) as a white solid: mp 223 °C (dec); IR #max (Nujol)/cm-1 <BR> <BR> <BR> 3332,3157,3071,2925,2852,1666,1510,1462,1377 and 724; NMR 6H (400 MHz, DMSO-d6) 0.81 (3H, t, J 7.2 Hz), 1.39 (2H, m), 1.56-1.69 (11H, br m), 1.96 (3H, m), 2.13 (1H, m) and 9.08 (4H, br m); NMR 6c (100 MHz, DMSO-d6) 11.8,17.0,27.8, 34.1,36.2,39.5,56.0 and 171.0.

Example 16 2-(1-Adamantyl)-3-phenylpropanimidamidehydrochloride This was prepared from 2-(1-adamantyl)-2-phenylpropanenitrile by the method of example 15 and the title compound (0.11 g, 46 %) isolated as a white crystalline solid: mp 147 - 148 °C ; IR #max (Nujol)/cm-1 3250 br, 2923,2852,1679,1495,1456,1377, <BR> <BR> <BR> 1346,1313,1084,739 and 699; NMR 5H (400 MHz, DMSO-d6) 1.51 (3H, ion), 1.66

(6H, m), 1.79 (3H, ion), 2.01 (3H, ion), 2.60 (1H, m), 2.96 (2H, m), 7.24 (5H, m), 8.60 (1H, br s), 8.78 (1H, br s), 8.92 (1H, br s) and 9.05 (1H, br s).

Example 17 3- (1-Adamantyl)-2-phenylpropanimidamide hydrochloride 3-(1-Adamantyl)-2-phenylpropenenitrile A solution of diethyl 1-cyano-1-phenylmethylphosphonate (10.97 g, 43.3 mmol) in dry THF (60 mL) at 0 °C was treated with NaH (60 % dispersion in oil, 1.7 g, 43.3 mmol), stirred at 0 °C for 40 min, warmed to room temperature for 20 min, treated with a solution of 1-adamantanecarboxaldehyde (3.56 g, 21.7 mmol) in dry THF (10 mL) and heated at 60 °C for 16 h. The rection mixture was cooled, treated with water (50 mL), extracted with EtOAc (3 x 20 mL), the extracts washed with brine (40 mL), dried (MgS04) and concentrated in vacuo. The resulting brown oil was purifie by <BR> <BR> <BR> <BR> chromatography [Si02, heptane-EtOAc (9: 1)] and recrystallised (heptane) to give the product (1.62 g, 28 %) as a white solid: mp 107 - 108 °C ; IR #max (Nujol)/cm-1 2924, <BR> <BR> <BR> <BR> 2852,2218,1497,1448,1377,1343,1101,910,762,750 and 689; NMR aH (400 MHz, CDC13) 1.76 (6H, ion), 1.99 (6H, m), 2.07 (3H, ion), 6.50 (1H, s), 7.37 (3H, m) and 7.51 (2H, m); Anal. Calcd for Cl9H2, N: C, 86.65; H, 8.04; N, 5.32. Found: C, 86.58; H, 8.09; N, 5.33.

3-(1-Adamantyl)-2-phenylpropanenitrile A solution of 3-(1-adamantyl)-2-phenylpropenenitrile (600 mg, 2.28 mmol) in EtOAc (30 mL) was treated with 10 % Pd/C (70 mg), hydrogenated at 50 psi for 16 h, filtered <BR> <BR> <BR> <BR> through Si02 and concentrated in vacuo. The residue was purifie by chromatography [Si02, EtOAc-heptane (1: 1)] and the resulting solid recrystallised (heptane) to give the product (552 mg, 91 %) as a white crystalline solid: mp 83 - 84 °C ; IR vmax (Nujol)/cm~l 2912,2852,2239,1497,1453,1377,1355,1346,1105,749,713 and 696; NMR 8H (400 MHz, CDCl3) 1.50 (1H, dd, J 14.3,3.2 Hz), 1.63 (9H, ion), 1.72 (3H, ion), 1.94 (1 H, dd, J 14.3,10.4 Hz), 2.01 (3H, ion), 3.79 (1H, dd, J 10.4,3.2 Hz) and

7.35 (SH, m); Anal. Calcd for ClgH23N: C, 85.99; H, 8.73; N, 5.28. Found: C, 85.96; H, 8.90; N, 5.27.

3-(1-Adamantyl)-2-phenylpropanimidamide(1-Adamantyl)-2-ph enylpropanimidamide hydrochloride This was prepared from 3-(1-adamantyl)-2-phenylpropanenitrile by the method of example 15 and the title compound (92 mg, 60 %) isolated as a pale brown solid: mp 253 °C (dec); IR vmax (Nujol)/cm~l 3243,2918,2853,1680,1496,1455,1377,1105, <BR> <BR> <BR> <BR> 1080,754,721 and 705; NMR OH (400 MHz, DMSO-d6) 1.40 (3H, m), 1.55 (7H, m), 1.68 (3H, m), 1.92 (3H, m), 2.15 (1H, m), 4.05 (1H, m), 7.31 (1H, m), 7.40 (2H, m), 7.52 (2H, m) and 9.01 (4H, br s).

Example 18 3-(1-Adamantyl)-3-phenylpropanimidamidehydrochloride This was prepared from 3-(1-adamantyl)-3-phenylpropanenitrile by the method of example 15 and the title compound (130 mg, 50 %) isolated as a pale yellow solid: mp 249 °C (dec) ; IR #max (Nujol)/cm-1 3400 - 2800 br, 2957,1684,1455,1407,1377,772 and 704; NMR aH (400 MHz, DMSO-d6) 1.37 (3H, m), 1.51 (6H, m), 1.60 (3H, m), 1.92 (3H, m), 2.91 (3H, m), 7.25 (5H, m), 8.50 (2H, br s) and 9.00 (2H, br s).

11 NMDA Receptor Binding The NMDA receptor contains several distinct binding domains that can regulate opening of the cationic channe. The phencyclidine (PCP) site of the NMDA receptor can be radiolabeled with [3H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10- imine hydrogen maleate, [3 H-MY,-801]. The following describes the procedure for determining the affinity of compound for the PCP site in rat cortical or cerebellar membranes.

Frozen rat cortex or cerebellum, homogenized in 10 volumes of ice cold 0.32 M. sucrose is centrifuged at 1,000 g for 12 min and the supernatant stored on ice whilst the

pellet was resuspended, rehomogenized and recentrifuged twice more. The three final supernatants were pooled and centrifuged at 30,000 g for 40 min at 4°C to yield P2 pellets. These were resuspended in ice-cold distille water, and centrifuged at 30,000 g for 50 min at 4°C. Following three further washes in distille water, the P2 pellets were stored at-20°C for at least 18h. On the day of the assay, membrane pellets were thawed at room temperature, resuspended in ice-cold distille water and centrifuged at 30,000 g for 20 min. The pellets were resuspended in 50 mM tris-cl (pH: 7.4) and recentrifuged twice more before being resuspended in tris-cl for immediate use in the assay. Binding assays were performed at equilibrium in a total volume of 200 1ll, containing, [3H]-MK- 801 (5 nM final conc.), 10 I1M glutamate, 10 pM glycine, 160 gel of membrane preparation and additional drugs where appropriate. Non-specific binding was determined using MK-801 (10 aux). The assay was incubated for 120 min at room temperature. The incubation was terminated by rapid filtration through Whatman GF/B filters (pre-soaked in 0.1% PEI solution). The assay tubes and filters were washed five times with lml of ice cold assay buffer. The filters were placed in poly-Q mini vials with approximately Sml of scintillation fluid. The vials are then shaken and left for at least 8 hours before being counted on a liquid scintillation conter. To determine the free ligand concentration 3 aliquots (20µl) of the [3H]-MK-801 working solution were also counted.

Concentration response data for drugs was analyse using a 4 parameter equation fitted by non linear regression. This yielded the half maximally effective drug concentration (ICso) and Hill coefficient.

The data obtained from these assays are presented in Table 1. The data clearly demonstrate that the compound of the invention are active as NMDA antagonists and have favorable ratios of cortical to cerebellar binding affinity indicating that the compound will be well-tolerated in vivo.

Table 1. Binding Affinités at Cortical and Cerebellar NMDA Receptors Compound RatioIC50(µM) Cortex Cerebellum Example 1 28 6 4.7 Example 2 291 Example 3 188 105 1.8 Example 4 122 56 2.2 Example 5 82 56 1.5 Example 6 31 Example 7 698 297 2.4 Example 8 1000 Example 9 754 388 1.9 Example 10 1000 Example 11 78 48 1.6 Example 12 96 36 2.7 Example 13 43 18 2.4 Example 14 406 234 1.7 Example 15 144 46 3.1 Example 16 52 27 1.9 Example 17 16 Example 18 27