WO2003064372A1 - 2-adamantylalkylamines et leur utilisation dans le traitement de troubles generalement associes a des anomalies de la transmission glutamatergique - Google Patents

2-adamantylalkylamines et leur utilisation dans le traitement de troubles generalement associes a des anomalies de la transmission glutamatergique Download PDF

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WO2003064372A1
WO2003064372A1 PCT/GB2003/000315 GB0300315W WO03064372A1 WO 2003064372 A1 WO2003064372 A1 WO 2003064372A1 GB 0300315 W GB0300315 W GB 0300315W WO 03064372 A1 WO03064372 A1 WO 03064372A1
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phenyl
adamantyl
alkyl
aryl
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Claire Elizabeth Dawson
Victoria Jane Ruston
Toby Jonathan Blench
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Ligand UK Research Ltd
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Vernalis Research Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to 2-adamantylalkylamines and their use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission.
  • the excitatory neurotransmission underlying brain function 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 function and plasticity. In view of the central role of these receptors in normal central nervous system function, numerous 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 and states of neuropathic pain.
  • Non-competitive antagonists at this receptor should be particularly advantageous in the treatment of diseases since such compounds 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.
  • NMDA antagonists which operate by binding to the ion- channel of the NMDA receptor.
  • the advantage 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 agonist.
  • 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 function within the brain. This may be manifested as central nervous system side effects such as hallucinations, confusion, paranoia, aggression, agitation and catatonia.
  • NMDA receptor antagonists that have efficacy in treating central nervous system disorders but without such psychotomimetic side effects would have a clear therapeutic advantage.
  • the present invention is particularly concerned with the treatment of neurodegenerative disorders and the treatment of pain.
  • 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.
  • antagonism of the NMDA receptor will reduce or prevent the neurodegeneration that underlies the disease process in these and related conditions (McCulloch et al., Acta Neurochir Suppl (Wien).
  • Neuropathic pain occurs during diabetic neuropathy, AIDS-related neuropathy, postherpetic neuralgia, chronic degenerative spinal disease, sympathetic dystrophies, post-amputation stump pain (phantom limb), trigeminal neuralgia, thalamic pain syndrome, sciatica and multiple sclerosis.
  • opiate tolerance Whilst pain due to cancer can be treated with opiate analgesics, the effect of opiates in producing pain relief in cancer diminishes with time. This phenomenon is known as opiate tolerance. Both pre-clinical and clinical studies have shown that NMDA antagonists prevent the development of opiate tolerance and have an "opiate sparing" effect. This means that administration of an NMDA antagonist alongside an opiate may result in the treatment of cancer pain using less opiate and with a more persistent effect.
  • Patent applications have been filed directed 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).
  • International Patent application WO94/05275 proposes the use of Amantadine and related compounds 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 Amantadine with alkyl groups was noted and published in Kornhuber et al. (Eur. J. Pharmacol., 1991, 206, 297-300).
  • NMDA antagonists such as Dizocilpine (MK-801), phencyclidine (PCP), Cerestat and Ketamine gives rise to a number of side effects which render these compounds unsuitable for use in treatment.
  • administration of the compounds is associated with perceptual and cognitive disturbances of a kind that resemble naturally-occurring psychotic states.
  • NMDA receptor channel blockers are frequently associated with the causation of psychotic states in clinical use.
  • the prototypical compound phencyclidine (PCP) when administered to man, usually achieves tissue levels similar to the potency of this compound in its action as an NMDA receptor channel blocker. Such tissue levels are associated with an acute psychotic state clinically indistinguishable from an acute schizophreniform breakdown.
  • administration of doses that produce equivalent tissue levels induces a characteristic behavioural state. This behavioural state comprises of the production of head weaving, circling, reciprocal fore paw treading and hyperactivity, as is known as the "PCP syndrome".
  • PCP syndrome The induction of the "PCP syndrome” is unique and specific to NMDA receptor channel blocking agents that are psychotomimetic in man.
  • Competitive antagonists acting at agonist binding sites on the NMDA receptor do not elicit this "PCP syndrome” and are not psychotomimetic in man.
  • Our data show that memantine, an NMDA receptor channel blocking agent, also elicits "PCP syndrome", as shown in Figure 1.
  • ketamine an NMDA receptor channel blocking agent with a similar binding potency to memantine, also produces "PCP syndrome” confirming that this syndrome reflects activity in a compound known to be psychotomimetic in man (see Figure 2).
  • a number of compounds 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 disease, as well as pain states. It has also been found that the compounds have a surprisingly favourable behavioural profile, being apparently devoid of the pre-clinical side effect liability associated with non-competitive blockers of the NMDA receptor channel.
  • X is oxygen or (CR u R 12 ) n ; n is 0 or 1 ; Ri, R 2 , R 3 , R 4 , R 5 , R ⁇ 5 , R 7 , R 8 , Rn and Rj 2 are independently selected from hydrogen, alkyl, aryl and non-aromatic heterocyclic groups, or each of one or more pair(s) thereof may together form a 3, 4, 5, 6, 7 or 8-membered ring containing 0, 1 or 2 heteroatom(s);
  • R is selected from alkyl, aryl and non-aromatic heterocyclic groups
  • R 10 is selected from hydrogen, halogen, alkyl, aryl and non-aromatic heterocyclic groups; and pharmaceutically acceptable salts and prodrugs thereof, in the manufacture of a medicament for use in the treatment of a condition generally associated with abnormalities in glutamatergic transmission.
  • the compounds of the present invention are active as NMDA antagonists and are well- tolerated in that side effects are minimised.
  • alkyl means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably C 3 to C 12 , more preferably C 3 to C , more preferably C 5 to C .
  • the alkyl group is preferably d to o, more preferably to C 6 , more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, tertiary-butyl or sec-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl.
  • alkyl as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl.
  • lower alkyl means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical, wherein a cyclic lower alkyl group is C 5 , C 6 or C 7 , and wherein an acyclic lower alkyl group is methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, tertiary-butyl or sec-butyl), more preferably methyl.
  • aryl means a carbocyclic aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, and preferably one, heteroatom(s) such as pyridyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, indazolyl, quinolinyl, quinazolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl and benzisothiazolyl.
  • the aryl group comprises
  • carbocyclic group refers to a ring wherein all the ring atoms are carbon atoms.
  • non-aromatic heterocyclic group refers to a ring or ring system which contains one or more heteroatom(s) (preferably heteroatoms(s) selected from N, O and S) and which is either saturated or partially unsaturated, such as piperidine, piperazine, morpholine, aziridine, azetidine, pyrrolidine, pyrroline or tetrahydrofuran.
  • partially unsaturated refers to a ring which contains unsaturated ring atoms but which is not aromatic. In a preferred embodiment, the term “partially unsaturated” refers to a ring which contains one or two double bonds.
  • alkoxy means alkyl-O-.
  • aryloxy means aryl-O-.
  • halogen means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical.
  • pharmaceutically acceptable salt means any pharmaceutically acceptable salt of the compound of formula (1). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic, ethanesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
  • Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
  • prodrug means any pharmaceutically acceptable compound which undergoes biotransformation to a compound of formula (1) prior to exhibiting it's pharmacological effects.
  • the use of prodrugs is widely described in the literature and the term “prodrug” has been defined by many authors for example in Burger's Medicinal Chemistry and Drug Design, 5 th Edition, 1995, Ed. M.E. Wolff, Nol 1, Principles and Practice, Pages 172 and 950.
  • Many molecules which possess the optimal structural configuration and physicochemical properties for eliciting the desired pharmacological action and therapeutic effect do not possess the best molecular form and properties for delivery to the desired site of action.
  • prodrug By attaching a "pro-moiety" to the "active moiety” a prodrug is formed that is designed to overcome the barrier which hinders the optimal use of the active principle.
  • the prodrug contains a covalent link between the "active moiety” and the “carrier moiety” which cleaves by biotransformation to release the "active moiety” after being absorbed into the body.
  • Chemical modification of drugs into prodrugs can often improve the physicochemical properties such as water-solubility and lipophilicity and transport of the drug to its site of action leading to improved bioavailability.
  • the use of prodrugs for amines is well known and has been reviewed in the literature for example by Pitman (Med. Res. Rev., 1981, 1, 189-214).
  • the term “treatment” includes prophylactic treatment. In a preferred embodiment, the term “treatment” includes the reduction or prevention of the progression of the condition to be treated, particularly where this condition is a neurodegenerative disease.
  • Ri to R 12 is an alkyl group as defined in formula (1) above, then that alkyl group may be substituted or unsubstituted. Where any of Ri to R 12 is an aryl group as defined in formula (1), then said aryl group may be substituted or unsubstituted. Where any of Ri to R 12 is a non-aromatic heterocyclic group as defined in formula (1), then said non-aromatic heterocyclic group may be substituted or unsubstituted. Where any pair of substituent groups selected from Ri to R 8 and Rn and R 12 togetlier form a ring, said ring may be substituted or unsubstituted.
  • Substituents may include: carbon-containing groups such as alkyl, aryl, (e.g. substituted and unsubstituted phenyl), arylalkyl; (e.g. substituted and unsubstituted benzyl); halogen atoms and halogen containing groups such as haloalkyl (e.g. trifluoromethyl), haloaryl (e.g. chlorophenyl); oxygen containing groups such as alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl,
  • aryl(hydroxy)alkyl ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, alkoxyaryl, aryloxyaryl), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl, arylalkylcarbonyl, arylalkylcarbonylalkyl, arylalkylcarbonylaryl) acids (e.g. carboxy, carboxyalkyl, carboxyaryl), acid derivatives such as esters
  • amines e.g. amino, mono- or dialkylamino, arylamino, aminoalkyl, mono- or dialkylaminoalkyl
  • azides e.g. cyano, cyanoalkyl
  • sulfur containing groups such as thiols, thioethers, sulfoxides, and sulfones
  • alkylthio alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl) and heterocyclic groups containing one or more, preferably one, heteroatom,
  • thienyl furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl,
  • condition generally associated with abnormalities in glutamatergic transmission refers particularly to conditions treatable by blockade of the N-methyl-D-aspartate (NMDA) receptor, i.e. conditions in which administration of an NMDA receptor antagonist would be beneficial, and primarily includes ischaemic stroke, haemorrhagic stroke, subarrachnoid haemorrhage, subdural haemafoma, 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, perinatal asphyxia, demyelinating disease, multiinfarct dementia, vascular dementia, dementia pugilans, drug dependence, alcohol withdrawal, opiate withdrawal, motor neurone disease, multiple sclerosis, acute and chronic pain including neuropathic pain, cancer
  • NMDA N-methyl
  • the term also includes the following conditions: epilepsy, AIDS dementia, 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, meningitis, encephalitis, depression, bi-polar disorder, schizophrenia, psychosis, behaviour disorders, impulse control disorders, pre-eclampsia, neuroleptic malignant syndrome, chronic fatigue syndrome, anorexia nervosa, anxiety disorders, generalised anxiety disorder, panic disorder, phobias, fresh water drowning and decompression.
  • the conditions are selected from Alzheimer's disease, ischaemic stroke, haemorrhagic stroke, epilepsy, multiple sclerosis, pain, drug-induced optic neuritis, myelopathy, glaucoma, peripheral neuropathy, ischaemic retinopathy.
  • the conditions are selected from traumatic brain or spinal injury, Parkinson's Disease and Huntington's Disease.
  • the conditions are selected from dementia (including senile dementia, multi-infarct dementia, vascular dementia and AIDS-dementia), drug dependence, alcohol withdrawal and opiate withdrawal.
  • the compounds of formula (1) are selected from compounds wherein K R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 , R 8 , R and R 12 are independently selected from hydrogen, alkyl and aryl, or each of one or more pair(s) thereof may together form a 3, 4, 5, 6, 7 or 8-membered ring containing 0, 1 or 2 heteroatom(s); R is selected from alkyl and aryl; and R 10 is selected from hydrogen, halogen, alkyl and aryl.
  • R l5 R 2 , R 3 , t , R 5 , R 6 , R 7 , R 8 , Rn and R 12 are independently selected from hydrogen and alkyl, and preferably hydrogen.
  • any of Ri, R 2 , R 3 , t , R 5 , Re, R , R 8 , Rn and R I2 is selected from alkyl
  • said alkyl group is a lower alkyl group, and preferably an acyclic lower alkyl group, and preferably methyl.
  • at least one of Ri and R 2 is hydrogen or methyl, preferably hydrogen, and preferably both R t and R 2 are hydrogen.
  • R is hydrogen and R 2 is lower alkyl, preferably methyl.
  • R 3 and t is/are hydrogen or methyl, preferably hydrogen, and more preferably both are hydrogen.
  • both of R 3 and j are methyl.
  • R 3 is hydrogen and ⁇ is methyl.
  • R 5 and R ⁇ is/are hydrogen or methyl, preferably hydrogen, and more preferably both are hydrogen.
  • R and Rg is/are hydrogen or methyl, preferably hydrogen, and more preferably both are hydrogen.
  • X is (CRnR 12 ) classroom.
  • X is (CRn i2) n
  • n is 0.
  • Rn and R 12 are hydrogen or methyl, preferably hydrogen, and more preferably both are hydrogen.
  • R 9 is selected from alkyl and aryl, preferably from cycloalkyl, unsubstituted acyclic alkyl (preferably lower alkyl), aryl-substituted acyclic alkyl (preferably lower alkyl) and aryl; and preferably from unsubstituted acyclic alkyl (preferably lower alkyl) and aryl; and more preferably from aryl.
  • R is selected from cycloalkyl, unsubstituted acyclic alkyl (preferably lower alkyl), acyclic alkyl (preferably lower alkyl) substituted by a non-aromatic heterocyclic group, aryl-substituted acyclic alkyl (preferably lower alkyl), non-aromatic heterocyclic groups, and aryl; preferably from unsubstituted alkyl (preferably acyclic, preferably lower alkyl), alkyl (preferably acyclic, preferably lower alkyl) substituted by a nonaromatic heterocyclic group, alkyl (preferably acyclic, preferably lower alkyl) substituted by aryl, non-aromatic heterocyclic groups, and aryl; and more preferably from unsubstituted alkyl (preferably acyclic, preferably lower alkyl), alkyl (preferably acyclic, preferably lower alkyl) substituted by aryl, and aryl; and more
  • R is selected from aryl or aryl-substituted alkyl
  • reference to said aryl specifically includes reference to heteroaromatic groups.
  • R 9 is selected from aryl or aryl- substituted alkyl, said aryl is preferably a carbocyclic aromatic group.
  • R 9 is selected from monocyclic substituted or unsubstituted, preferably unsubstituted, aryl (including heteroaromatic groups).
  • R 9 is a substituted or unsubstituted carbocyclic aromatic group, preferably unsubstituted, preferably phenyl.
  • R 9 is an heteroaromatic group, it is preferred that R contains only one heteroatom.
  • R 9 is thienyl (including 2-thienyl), thiazolyl (including 2-thiazolyl), pyridyl (including 2-pyridyl) or furyl (including 2-furyl); preferably thienyl (including 2-thienyl), pyridyl (including 2-pyridyl) or furyl (including 2-furyl); more preferably thienyl; and more preferably 2-thienyl.
  • R is substituted aryl, particularly substituted phenyl
  • substituent group preferably selected from alkyl (including haloalkyl such as CF 3, and preferably lower alkyl, more preferably lower acyclic alkyl, more preferably methyl), halogen (preferably fluoro or chloro), alkoxy (preferably lower alkoxy, more preferably lower acyclic alkoxy, more preferably methoxy); and more preferably selected from alkyl (including haloalkyl such as CF 3j and preferably lower alkyl, more preferably lower acyclic alkyl, more preferably methyl) .
  • R is preferably alkyl substituted by aryl.
  • R is preferably selected from aryl-substituted alkyl, particularly benzyl or pyridyl methyl (including (4-pyridyl)methyl, (3-pyridyl)methyl and (2-pyridyl)methyl) and preferably benzyl.
  • R 9 is a non-aromatic heterocyclic group
  • R may be selected from 5 and 6-membered non-aromatic heterocyclic groups, preferably containing 1 or 2 heteroatoms, preferably only one heteroatom, and preferably selected from N, O and S, preferably N and O, and more preferably O.
  • said non-aromatic heterocyclic group is saturated.
  • R 10 is selected from hydrogen, halogen, alkyl, aryl and non-aromatic heterocyclic groups. In one embodiment, R 10 is selected from hydrogen, alkyl, aryl and non-aromatic heterocyclic groups. In an alternative embodiment, R 10 is selected from hydrogen, halogen, alkyl and aryl. In a further embodiment, R 10 is selected from hydrogen, alkyl and aryl. Preferably, R 10 is selected from hydrogen and alkyl, and is preferably hydrogen. Where R 10 is selected from alkyl, it is preferred that R 10 is selected from lower alkyl, and preferably acyclic lower alkyl.
  • each of one or more pair(s) of the substituent groups R 1; R 2 , R 3 , R , R 5 , R ⁇ , R , R 8 , Rn and R 12 may together form a 3, 4, 5, 6, 7 or 8 membered ring, preferably a 3, 4, 5, or 6 membered ring.
  • each of one or more pair(s) of R ls R 2 , R 3 , R t , R 5 , R ⁇ R 7 , Rs, Rn and R 1 may together form a 5, 6 or 7 membered ring, more preferably a 5 or 6 membered ring.
  • each of one or more pair(s) of substituent groups selected from Ri and R 2 ; R 3 and R4; R 5 and Re ; R 7 and R 8 ; and Rn and R 12 may together form a 3, 4, 5, 6, 7 or 8 membered ring.
  • each of one or more pair(s) of groups selected from Ri or R 2 together with R 3 or R 4 ; Ri or R together with R 5 or R ⁇ R or R 2 together with R or R 8 ; Ri or R 2 together with Rn or R 12 ; R 3 or R t together with R 5 or R ⁇ R 3 or R 4 together with R 7 or R 8 ; R 3 or t together with R or R 12 ; R 5 or Re together with R 7 or R 8 ; R 5 or R ⁇ together with Ri ] or R 12 ; and R 7 or R 8 together with R ⁇ ⁇ or R 12 may form a 3, 4, 5, 6, 7 or 8 membered ring.
  • the ring may be saturated, partially unsaturated or aromatic, preferably saturated or partially unsaturated, and more preferably saturated. It will be appreciated that the formation of an aromatic ring by cyclisation of the substituent groups R ls R 2 , R , R ⁇ t, R 5 , e, R , R 8 , Rn and R 12 is equivalent to the cyclisation of a plurality of pairs of these groups, for example cyclisation of R 3 and j with R 2 and Ri forms a pyridyl ring.
  • a ring formed by a pair of the substituent groups R l5 R 2 , R 3 , R4, R5, Re, R 7 , R&, Rn and R 12 contains 0, 1 or 2 heteroatom(s).
  • the heteroatoms are selected from N, O and S, and in one embodiment from N and O.
  • a ring contains heteroatom(s)
  • it is preferred that said ring contains only one heteroatom.
  • the ring may optionally contain one or two heteroatom(s).
  • X is (CR 11 R 12 ) n and a ring is formed between R 3 or R 4 or R 5 or e and R or R 8 or Rn or R 12 ; or between R 7 or R 8 and R or R 12 , the ring may optionally contain one or two heteroatom(s).
  • the ring may optionally contain one additional heteroatom.
  • the ring may optionally contain one additional heteroatom.
  • the ring may optionally contain one additional heteroatom.
  • the ring may optionally contain one additional heteroatom.
  • the ring may optionally contain one additional heteroatom.
  • substituent groups Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Rn and R 12 together form a 3, 4, 5, 6, 7 or 8 membered ring.
  • said one pair of substituent groups is selected from R l3 R 2 , R 3 , R t , R 5 , R ⁇ s, Rn and R 12 . Further preferred pairs of substituent groups between which there is ring formation are set out below.
  • Ri and R 2 together fonn a 4, 5, 6, 7 or 8 membered ring, preferably a 5 or 6 membered ring, preferably saturated, and optionally containing one additional heteroatom, preferably N or O, and preferably O.
  • X may be either O or (CRnR 12 )n as defined herein.
  • X may be either O or (CRnR 12 ) n as defined herein.
  • R 3 and R together form a 3, 4, 5, 6, 7 or 8-membered ring, preferably a 3 or 4-membered ring, particularly wherein X is (CRi ⁇ Ri 2 ) n -
  • Ri or R 2 together with Rn or R 12 form a 6, 7 or 8-membered ring.
  • X is CR R ⁇ 2 , R 3 or R 4 together with Rn or R 12 form a 4, 5, 6, 7 or 8-membered ring, preferably a 4 or 6-membered ring.
  • the compounds of formula (1) do not include compounds wherein either of the substituent groups R or R 10 form cyclic moieties by cyclisation with each other or with any of R ⁇ to R 8 , Rn and R 12 . Equally, it will be appreciated that the compounds of formula (1) do not include compounds wherein either of R or R 10 form cyclic moieties with any other part of the molecule. As noted above, compounds of formula (1) do, however, include compounds wherein either of R 9 or R 10 is itself a cyclic group, such as a cycloalkyl group or an aryl group.
  • the compounds 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 includes a reference to the unseparated stereoisomers in a mixture, racemic or non-racemic, and to each stereoisomer in its pure form.
  • the compound of formula (1) is selected from the group consisting of:
  • the compounds are selected from:
  • the present invention also 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 the formula (1) as defined above, and pharmaceutically acceptable salts and prodrugs thereof.
  • the present invention also provides, for use in therapy, a compound of the formula (1) as defined above and pharmaceutically acceptable salts and prodrugs thereof.
  • the present invention also provides a compound of the formula (1) as defined above, and pharmaceutically acceptable salts and prodrugs thereof, per se, other than 3-[2-[2- bromomethyl]adamantyl]propylamine and 3- [2- [2-(2-aminoethyl)] adamantyljpropylamine, preferably other than compounds wherein R is alkyl substituted by any group other than aryl, more preferably other than compounds wherein R is substituted alkyl, and more preferably other than compounds wherein R is alkyl.
  • the present invention provides a compound of the formula (1) as defined above, and pharmaceutically acceptable salts and prodrugs thereof, per se, wherein R is selected from aryl and non-aromatic heterocyclic groups, and preferably aryl, as defined above.
  • Compounds of formula (2) may be prepared from amines (3) by standard methods such as alkylation, reductive alkylation, acylation/reduction, or arylation (for example by palladium-catalysed coupling to aryl halides).
  • Amines (3) may be prepared from nitro compounds (4) where R 4 is H by standard methods such as reduction with LiAlH .
  • Nitro compounds (4) may be prepared from aldehydes (5) by standard methods such as condensation with a nitroalkane in the presence of a suitable base, followed by acylation and reductive elimination for example by treatment with acetic anhydride and then sodium borohydride.
  • Aldehydes (5) may be prepared from alkenes (6) by standard methods such as oxidative cleavage for example by ozonolysis.
  • Alkenes (6) may be prepared from alcohols (7) by standard methods such as treatment with allyltrimethylsilane in the presence of BF 3 .
  • the preparation of alcohols (7) is described in the literature.
  • Compounds of formula (8) may be prepared from amines (9) by standard methods such as alkylation, reductive alkylation, acylation/reduction or arylation as described above.
  • Amines (9) may be prepared from nitro compounds (10) by standard methods such as reduction with LiAlFL t .
  • Nitro compounds (10) may be prepared from nitro compounds (4) by standard methods such as alkylation in the presence of a suitable base. Nitro compounds (10) where R 3 and R together form a ring may be prepared from nitro compounds (4) where t is H by double alkylation in the presence of a suitable base. Nitro compounds (4) may be prepared as described above. Reaction Scheme 1
  • Aldehydes (11) where R 6 is H may be prepared from esters (12) by standard methods such as reduction with DIBAL.
  • Ketones (11) may be prepared from esters (12) by standard methods such as treatment with an appropriate Grignard reagent or an alkyl or aryl lithium reagent.
  • Esters (12) may be prepared from alcohols (7) by standard methods such as treatment with a silyl ketene acetal, for example methyl trimethylsilyldimethylketene acetal, in the presence of a Lewis acid such as BF 3 .
  • a Lewis acid such as BF 3 .
  • aldehydes (11) where Re and R 7 are H or ketones (11) where R is H may be prepared from aldehydes (13) where R 8 is H or ketones (13) by standard methods such as Wittig reaction with an alkoxymethyl phosphonium salt in the presence of a suitable base, followed by hydrolysis of the intermediate enol ether.
  • esters (12) may be prepared from esters (14) by standard methods such as alkylation in the presence of a strong base.
  • Esters (12) where R 7 and R 8 together form a ring may be prepared from esters (14) by double alkylation as described above.
  • the preparation of esters (14) is described in the literature.
  • Compounds of formula (15) may be prepared from amines (16) by standard methods such as alkylation, reductive alkylation, acylation/reduction or arylation as described above.
  • Amines (16) may be prepared from unsaturated nitriles (17) by standard methods such as catalytic hydrogenation.
  • Unsaturated nitriles (17) may be prepared from aldehydes (13) where R 8 is H or ketones (13) by standard methods such as Wadsworth-Emmons reaction with a cyanomethylphosphonate in the presence of a suitable base.
  • the preparation of aldehydes (13) where R is H and ketones (13) is described in the literature.
  • Compounds of formula (18) may be prepared from aldehydes (19) where R 4 is H or ketones (19) by standard methods such as reductive amination with an appropriate amine.
  • Aldehydes (19) where t is H may be prepared from nitriles (20) by standard methods such as reduction with DIBAL followed by hydrolysis of the intermediate imine.
  • Ketones (19) may be prepared from nitriles (20) by standard methods such as treatment with an appropriate Grignard reagent or an alkyl or aryl lithium reagent followed by hydrolysis.
  • Nitriles (20) may be prepared from nitriles (21) by standard methods such as alkylation in the presence of an appropriate base.
  • Nitriles (21) may be prepared from unsaturated nitriles (17) by standard methods such as reduction with sodium borohydride. Unsaturated nitriles (17) may be prepared as described above.
  • Compounds of formula (22) may be prepared from amines (23) by standard methods such as alkylation, reductive alkylation, acylation/reduction or arylation as described above.
  • Amines (23) may be prepared from alcohols (24) by standard methods such as converting the alcohol into a mesylate, followed by treatment with an azide salt and then reduction by standard methods such as Staudinger reaction.
  • Alcohols (24) may be prepared from ketones (19) by standard methods such as reaction with an appropriate Grignard reagent or an alkyl or aryl lithium reagent.
  • Ketones (19) may be prepared as described above. Reaction Scheme 3
  • Compounds of formula (25) may be prepared from nitro compounds (26) using the method described for the conversion of nitro compounds (4) into compounds of formula (8) (Reaction Scheme 1).
  • Nitro compounds (26) may be prepared from aldehydes (27) where Re is H or ketones (27) by standard methods such as condensation with a nitroalkane in the presence of a suitable base, followed by acylation and reductive elimination for example by treatment with acetic anhydride and then sodium borohydride.
  • Aldehydes (27) where Re is H and ketones (27) may be prepared from aldehydes (11) where R 12 is H or ketones (11) by standard methods such as Wittig reaction with an alkoxymethyl phosphonium salt in the presence of a suitable base, followed by hydrolysis of the intermediate enol ether.
  • Aldehydes (11) where R 12 is H or ketones (11) may be prepared as described above.
  • Compounds of formula (28) may be prepared from nitriles (29) using the method described for the preparation of compounds of formula (22) from nitriles (20) (Reaction Scheme 3).
  • compounds of formula (28) may be prepared from amines (28) where Ri and R 2 are H as described above for the preparation of compounds (22) from amines (23).
  • Amines (28) where Ri and R 2 are H may be prepared from the corresponding alcohols as described above for the preparation amines (23) from alcohols (24).
  • the alcohols may be prepared from the corresponding ketones as described above for the preparation of alcohols (24) from ketones (19).
  • the ketones may be prepared from nitriles (29) as described above for the preparation of ketones (19) from nitriles (20).
  • Nitriles (29) may be prepared from nitriles (30) as described above for the preparation of nitriles (20) from nitriles (21).
  • Nitriles (30) may be prepared from unsaturated nitriles (31) by standard methods such as a Michael reaction with an appropriately metallated alkyl or aryl reagent.
  • Unsaturated nitriles (31) may be prepared from aldehydes (11) where R 12 is H or ketones (11) by standard methods such as Wadsworth-Emmons reaction with a cyanomethylphosphonate as described above.
  • Aldehydes (11) where R 12 is H or ketones (11) may be prepared as described above.
  • Compounds of formula (32) may be prepared from alcohols (33) by standard methods such as treatment with an appropriately substituted ethanolamine under Mitsunobu conditions.
  • Alcohols (33) may be prepared from aldehydes (13) where R 8 is H or ketones (13) by standard methods such as reduction with sodium borohydride.
  • Aldehydes (13) where R 8 is H and ketones (13) may be prepared as described above.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the formula (1), or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable excipient.
  • the compound of formula (1) may be administered in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; 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 or nasal drops; for vaginal or rectal use, for example a suppository; 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; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oil solution or suspension, or depot injection formulation.
  • the above compositions may be prepared in a conventional manner using convention excipients, using standard techniques, including controlled release technologies, such as gelatin, lipid, gel depot
  • the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
  • Tablets 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, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl- pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • Transdermal formulations include membrane permeation systems, multi-laminate adhesive dispersion systems and matrix dispersion systems. Transdermal delivery also includes the use of electrically aided transport and skin penetration enhancers.
  • 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 styrette or as a subcutaneous injection.
  • a daily dosage of the active constituent is 100 ⁇ g to 800 mg. More particularly the preferred compounds may be administered at a preferred dose of 50-800 mg daily in single or divided doses.
  • GC retention times were recorded using a Perkin Elmer Autosystem XL GC with FID detector: Column: SGE 25QC2/BP1 0.25; Carrier gas: Helium; Temperature program: 150 °C to 320 °C at 10 7min, isothermal for 8 min at 320 °C; Detection method: FID Hydrogen and air; Injection: approx 2 ⁇ L at 10 mg/mL in chloroform with 10:1 split.
  • the NMDA receptor contains several distinct binding domains that can regulate opening of the cationic channel.
  • the phencyclidine (PCP) site of the NMDA receptor can be radiolabeled with [ 3 H]-(+)-5-methyl-10,l l-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine hydrogen maleate, ([ 3 H]-MK-801).
  • PCP phencyclidine
  • Frozen rat cortex 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 is resuspended, rehomogenized and recentrifuged twice more. The three final supernatants are pooled and centrifuged at 30,000 g for 20 min at 4°C to yield P pellets. These are resuspended in ice- cold 5 mM Tris-HCl (pH 7.5) and centrifuged at 30,000 g for 20 min at 4°C. Following tliree further washes in distilled water, the P 2 pellets are stored at -80°C for at least 18 h.
  • membrane pellets are thawed at room temperature, resuspended in ice-cold 5 mM Tris-HCl (pH 7.5) and centrifuged at 30,000 g for 20 min. This wash step is repeated three more times and the final pellet is resuspended in assay buffer (5 mM Tris- HCl, pH 7.5) for immediate use in the assay.
  • Binding assays are performed at equilibrium in a total volume of 250 ⁇ l, containing [ H]-MK-801 (2 nM final cone), in addition a cocktail of allosteric modulators is also included: (50 ⁇ M glutamate, 30 ⁇ M glycine and 50 ⁇ M spermidine), 200 ⁇ L of membrane preparation and additional drugs where appropriate. Non-specific binding is determined using MK-801 (10 ⁇ M).
  • the assay is incubated for 60 min at room temperature. The incubation is terminated by rapid filtration through Unifilter GF/B filters (pre-soaked in 0.1% PEI solution) using a Canberra Packard filtermate. MicroScint-20 is then added to the filters and are left for at least 2 hours before counting.
  • Figure 1 shows the behavioural profile of memantine administered intraperitoneally at doses of 5, 10, 20 and 40 mg/kg twenty minutes prior to test.
  • Figure 2 shows the behavioural profile of ketamine administered intraperitoneally at doses of 10, 20, 40 and 80 mg/kg twenty minutes prior to test.

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Abstract

L'invention se rapporte à l'utilisation d'un composé représenté par la formule (I), où : X représente oxygène ou (CR11R12)n ; n est égal à 0 ou 1 ; R1, R2, R3, R4, R5, R6, R7, R8, R11 et R12 sont sélectionnés indépendamment parmi hydrogène, les groupes alkyle, aryle et hétérocycliques non aromatiques, ou chaque paire formée par ceux-ci peuvent, ensemble, former un anneau à 3, 4, 5, 6, 7 ou 8 éléments contenant 0, 1 ou 2 hétéroatomes ; R9 est sélectionné parmi les groupes alkyle, aryle et hétérocycliques non aromatiques ; et R10 est sélectionné parmi hydrogène, halogène, les groupes alkyle, aryle et hétérocycliques non aromatiques. L'invention concerne également des sels pharmaceutiquement acceptables et des promédicaments à usage thérapeutique dudit composé, et la production d'un médicament destiné à être utilisé dans le traitement d'un trouble généralement associé à des anomalies de la transmission glutamatergique, en particulier la maladie d'Alzheimer, l'accident vasculaire cérébral ischémique, l'accident vasculaire cérébral hémorragique, l'épilepsie, la sclérose en plaques, la douleur, la névrite optique induite par un médicament, la myélopathie, le glaucome, la neuropathie périphérique, la rétinopathie ischémique, les traumatismes crâniens ou médullaires, la maladie de Parkinson et la maladie de Huntington. L'invention a également trait aux nouveaux composés représentés par la formule (I) eux-mêmes.
PCT/GB2003/000315 2002-01-30 2003-01-27 2-adamantylalkylamines et leur utilisation dans le traitement de troubles generalement associes a des anomalies de la transmission glutamatergique Ceased WO2003064372A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5061703A (en) * 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
WO1994005275A1 (fr) * 1992-09-03 1994-03-17 The Children's Medical Center Corporation Procede de prevention contre les lesions neuronales dues au recepteur nmda
US5599998A (en) * 1994-10-24 1997-02-04 Iowa State University Research Foundation, Inc. Method for the synthesis of adamantane amines
US6262106B1 (en) * 1998-02-02 2001-07-17 Vernalis Research Limited Adamantanecarboximidamide derivatives and their use as NMDA antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5061703A (en) * 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
WO1994005275A1 (fr) * 1992-09-03 1994-03-17 The Children's Medical Center Corporation Procede de prevention contre les lesions neuronales dues au recepteur nmda
US5599998A (en) * 1994-10-24 1997-02-04 Iowa State University Research Foundation, Inc. Method for the synthesis of adamantane amines
US6262106B1 (en) * 1998-02-02 2001-07-17 Vernalis Research Limited Adamantanecarboximidamide derivatives and their use as NMDA antagonists

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