Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • 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
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D215/14—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/18—Halogen atoms or nitro radicals

Definitions

• This invention relates to an enantiomer of ( ⁇ ) E 4-(4-Acetylamino- phenylcarbamoylmethylene)-5,7-dichloro-1 ,2,3,4-tetrahydro quinoline 2- 5 carboxylic acid a potent and specific antagonist of excitatory amino acids, to processes for preparing the same, to pharmaceutical compositions containing it, to its use in medicine.
• WO 97/12870 describes inter alia ( ⁇ ) E 4-(4-Acetylamino- 10 phenylcarbamoylmethylene)-5,7-dichloro-1 ,2,3,4-tetrahydro quinoline - 2-carboxylic acid (A)
• (+) enantiomer exhibits a particular useful profile of activity as a selective antagonist for the strychnine insensitive glycine binding site on the NMDA receptor complex.
• the present invention thus provides the (+) enantiomer of (E) 4-(4- acetylamino-phenylcarbamoylmethylene)-5,7-dichloro-1 ,2,3,4-tetrahydro quinoline 2-carboxylic acid (hereinafter compound (I)) and salts thereof, substantially free of the corresponding (-) enantiomer.
• compound (I) substantially free as used herein means that compound (I) contains less than 10% of the (-) enantiomer and preferably less than 5%.
• (+) enantiomer as used herein refers to the specific enantiomer which is the product of examples 2, 4 and 5.
• references to salts include both physiologically acceptable salts and non-physiologically acceptable salts of compound (I).
• Suitable physiologically acceptable salts of compounds of the invention include base addition salts.
• Suitable physiologically acceptable base addition salts of compound (I) include alkali metal or alkaline earth metal salts such as sodium, potassium, calcium, and magnesium, and ammonium salts, formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
• alkali metal or alkaline earth metal salts such as sodium, potassium, calcium, and magnesium
• ammonium salts formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
• a preferred salt of compound (I) is the sodium salt.
• the compound of the invention and/or physiologically acceptable salts thereof are excitatory amino acid antagonists. More particularly they are potent antagonists at the strychnine insensitive glycine binding site associated with the NMDA receptor complex. As such it is a potent antagonist of the NMDA receptor complex.
• Compound (I) is therefore useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases.
• compound (I) is also useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, haemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia cardiac arrest.
• Compound I is also useful in the treatment of chronic neurodegenerative diseases such as Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodegeration (e.g. AIDS, encephalopaties), Down syndrome, epilepsy, schizophrenia, depression, anxiety, pain, neurogenic bladder, irritative bladder disturbances, migraine, headaches, including cluster headaches, tension headache, drug dependency, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine, benzodiazepine and emesis.
• chronic neurodegenerative diseases such as Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurode
• the potent and selective action of the compound of the invention at the strychnine- insensitive glycine binding site present on the NMDA receptor complex may be readily determined using conventional test procedures.
• the ability to bind at the strychnine insensitive glycine binding site was determined using the procedure of Kishimoto H et al. J Neurochem 1981 , 37 1015-1024.
• the selectivity of the action of compound (I) for the strychnine insensitive glycine site was confirmed in studies at other ionotropic known excitatory amino acid receptors.
• compound (I) was found to show little or no affinity for the kainic acid (kainate) receptor, ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor or at the NMDA binding site.
• kainate kainic acid
• AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid
• the compound of the invention has also been found to inhibit NMDA induced convulsions in mice using the procedure Chiamulera C. et al. Psychopharmacology (1990) 102, 551-552.
• the neuroprotective activity of the compound of the invention was demonstrated in the middle cerebral artery occlusion preparation in mice, using the procedure described by Chiamulera C. et al., European Journal of Pharmacology, 216 (1992) pp. 335-336.
• the invention therefore provides for the use of compound (I) and/or physiologically acceptable salt thereof for use in therapy and in particular use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
• the invention also provides for the use of compound (I) and/or a physiologically acceptable salt thereof for the manufacture of a medicament for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
• the invention also provides for a method for antagonising the effects of excitatory amino acids upon the NMDA receptor complex, comprising administering to a patient in need thereof an antagonistic amount of compound (I) and/or a physiologically acceptable salt.
• the amount of the compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to 800mg per day, dependent upon the route of administration.
• a daily dose will typically be in the range 20-800mg, preferably 60-800mg per day.
• a daily dose will typically be within the range 200-800mg, e.g. 400- 600mg per day.
• the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. While it is possible that, for use in therapy, compound (I) may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
• the invention thus further provides a pharmaceutical formulation comprising compound (I) or a physiologically acceptable salt thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients.
• the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhalation or insufflation, implant, or rectal administration. Parenteral administration is preferred.
• Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatine, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in the art.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p- hydroxybenz
• composition may take the form of tablets or lozenges formulated in conventional manner.
• composition according to the invention may be formulated for parenteral administration by injection or continuous infusion.
• Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
• the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
• inhalation compound (I) for administration by inhalation compound (I) according to the invention is conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro- tetrafluoroethane, carbon dioxide or other suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane, carbon dioxide or other suitable gases, or from a nebuliser.
• a suitable propellant such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro- tetrafluoroethane, carbon dioxide or other suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane, carbon dioxide or other suitable gases, or from
• the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable carrier such as lactose or starch.
• a suitable carrier such as lactose or starch.
• the powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
• composition according to the invention may also be formulated as a depot preparation.
• Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• compositions according to the invention may contain between 0.1 - 99% of the active ingredient, conveniently from 30- 95% for tablets and capsules and 3-50% for liquid preparations.
• the invention provides processes for the preparation of compound 1.
• compound (I) ((+)-E-4-(4- Acetylamino-phenylcarbamoylmethylene)-5,7- dichloro-1 ,2,3,4-tetra- hydroquinoline-2-carboxylic acid) may be prepared by esterification of compound A with a suitable chiral alcohol, separating the resultant diastereomeric esters by conventional means e.g. chromatography or crystallisation followed by hydrolysis of the required single diastereomeric ester.
• Suitable chiral alcohols for use in the process A include (+)S-indanol, (+)S-methyl mandelate, chiral (C1-4)alkyl lactate: i.e., (+)R or (-)S methly lactate, (+)R t-butyl lactate, (+)R or (-)S ethyl lactate, (-)S isopropyl lactate, (-)S butyl lactate, (+)R isobutyl lactate or chiral aralkyl lactate (i.e.
• diastereomeric esters of compound A including the single diastereomeric ester substantially free of the other diastereomeric are novel compounds and represent a further aspect of the invention
• the diastereomeric esters of compound A may be prepared by conventional means such as reaction of the chiral alcohol with an activated derivative of the compound A in an aprotic solvent such as ether e.g. tetrahydrofuran.
• the activated derivative of Compound A may be prepared from compound A using conventional means for preparing activated derivatives of a carboxylic acid groups such as those conveniently used in peptide synthesis.
• a particularly convenient method of preparing the diastereomeric esters of compound A is to prepare the activated derivative of compound A in the presence of the chiral alcohol.
• compound A may be treated with the Mitsunobu combination of reagents, i.e. a dialkyl azo-dicarboxylate such as diethylazodicarboxylate and a triarylphosphine e.g. triphenylphosphine or trialkylphoshine (i.e. tributylphosphine) in the presence of the chiral alcohol.
• reagents i.e. a dialkyl azo-dicarboxylate such as diethylazodicarboxylate and a triarylphosphine e.g. triphenylphosphine or trialkylphoshine (i.e. tributylphosphine) in the presence of the chiral alcohol.
• the reaction conveniently takes place in the presence of a suitable solvent such as an ether (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile (e.g. acetonitrile) or a mixture thereof at a temperature ranging from 0-30°.
• a suitable solvent such as an ether (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile (e.g. acetonitrile) or a mixture thereof at a temperature ranging from 0-30°.
• the required single diastereomeric ester of compound A substantially free of the other diastereomers may be obtained from the mixture thereof by conventional means, for example by the use of conventional chromatographic procedures such as preparative HPLC or by fractional crystallization.
• Compound (I) may be prepared from the corresponding single diastereomeric ester of compound A by hydrolysis e.g. alkaline hydrolysis.
• the hydrolysis may be carried using an alkali metal hydroxide e.g. sodium hydroxide or lithium hydroxide in a solvent such as an ether e.g. tetrahydrofuran and water.
• Compound (I) may be isolated as the free acid or as a salt thereof.
• Compound I may also be obtained from racemic compound A by use of chiral HPLC procedures.
• Compound (A) may be prepared by reaction of an activated derivative of the carboxylic acid (II) in which R 1 is a carboxylic acid protecting group and R 3 is hydrogen or a nitrogen protecting group
• the invention also provides a further process for the preparation of the compound (I) (hereinafter process B) which comprises reacting an activated derivative of the carboxylic acid (IV)) in which R 3 is hydrogen or a nitrogen protecting group and R 5 is a suitable chiral group with the amine (III). (IV)
• Suitable chiral groups (R 5 ) for use in the process B are those derived from chiral alcohols such as (+)S-indanol, (+)S-methyl mandelate, chiral (C1-4)alkyl lactate: i.e., (+)R or (-)S methly lactate, (+)R t-butyl lactate, (+)R or (-)S ethyl lactate, (-)S isopropyl lactate, (-)S butyl lactate, (+)R isobutyl lactate or chiral aralkyl lactate (i.e. benzyl lactate), (-)S perillyl alcohol, (-)methyl(R)-3-hydroxy-2-methylpropionate, (-)(R)-2-butanol, (-) (S)-2-methyl-1-butanol.
• chiral alcohols such as (+)S-indanol, (+)S-methyl mandelate, chiral (C1-4)al
• R 5 is preferably a group derived from a chiral (C1-4)alkyl lactate alcohol. More preferably R 5 is derived from (+)(R) t-butyl lactate alcohol.
• Suitable activated derivatives of the carboxylic acid group include the corresponding acyl halide, mixed anhydride, activated ester such as a thioester or the derivative formed between the carboxylic acid group and a coupling agent, such as that used in peptide chemistry, for example carbonyl diimidazole or a diimide, such as dicyclohexylcarbodiimide.
• the reaction is preferably carried out in an aprotic solvent, such as a hydrocarbon, a halohydrocarbon such as dichloromethane or an ether such as tetrahydrofuran.
• an aprotic solvent such as a hydrocarbon, a halohydrocarbon such as dichloromethane or an ether such as tetrahydrofuran.
• R 3 is a nitrogen protecting group
• suitable groups include alkoxycarbonyl, e.g. t-butoxycarbonyl, arylsulphonyl e.g. phenysulphonyl or 2-trimethylsilylethoxymethyl.
• Alkyl when used as substituent or a part of a substituent group means that the group may be straight or branched.
• C1-4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or ter-butyl.
• the activated derivatives of the carboxylic acid (IV) may be prepared by conventional means.
• a particularly suitable activated derivative for use in this reaction is thioester such as that derived from pyridine-2-thiol.
• These esters may conveniently be prepared by treating the carboxylic acid (II) with 2,2'-dithiopyridine and triphenylphosphine in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran, a halohydrocarbon e.g. dichloromethane, an amide e.g. N,N-dimethylformamide or acetonitrile.
• the appropriate diastereomeric derivative can be isolated by conventional means e.g. chromatography or by crystallisation.
• the hydrolysis step conveniently takes place using an alkali metal hydroxide e.g. sodium hydroxide or lithium hydroxide in a suitable solvent such as an ether i.e. tetrahydrofuran, water and a mixture thereof or alkali trialkylmethylsilanolate (e.g. trimethylsiianolate) followed, where desired or necessary, by the addition of a suitable acid e.g. hydrochloric acid to give the corresponding free carboxylic acid.
• a suitable solvent such as an ether i.e. tetrahydrofuran, water and a mixture thereof or alkali trialkylmethylsilanolate (e.g. trimethylsiianolate)
• a suitable acid e.g. hydrochloric acid
• R represents a bromine or iodine atom
• R 3 represents hydrogen or a nitrogen protecting group
• R 4 represents a hydrogen atom or a suitable carboxylic acid protecting group such as t-butyl group
• R represents R or R 5 as defined in formula (II) or formula (IV) respectively, followed by removal of the of carboxylic protecting group R 4 using conventional methods.
• the reaction may be carried out using a catalytic amount of a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium and a suitable organic base such as trialkylamine e.g. triethylamine or inorganic base, e.g. potassium carbonate.
• a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium
• a suitable organic base such as trialkylamine e.g. triethylamine or inorganic base, e.g. potassium carbonate.
• reaction is conveniently carried out in an aprotic solvent such as acetonitrile or dimethylformamide at a temperature with the range of 20°C to 150°C followed, where necessary or desired, by subsequent removal of the carboxylic acid protecting group R 4 and any protecting group R 3 .
• aprotic solvent such as acetonitrile or dimethylformamide
• the reaction is carried out using a catalytic amount of a Pd(ll) salt such as palladium acetate, in the presence of a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine.
• a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine.
• the reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide and preferably with heating, followed, where necessary or desired, by subsequent removal of the carboxylic acid protecting group R and any nitrogen protecting group R 3
• Compounds of formula (V) may be prepared by reacting a imino ester of formula(VI), wherein R 2 and R 6 have the meanings defined above, with a compound of formula (VII) in which R 7 represents a C1-4 alkyl group and R 4 is a hydrocarbysilyl group such as trialkylsilyl, e.g. trimethylsilyl or terbutyldimethylsilyl or a suitable carboxylic acid protecting group such as tert-butyl group, followed, if desired, by the conversion of the group NH into a nitrogen protecting group NR 3 .
• a compound of formula (VII) in which R 7 represents a C1-4 alkyl group and R 4 is a hydrocarbysilyl group such as trialkylsilyl, e.g. trimethylsilyl or terbutyldimethylsilyl or a suitable carboxylic acid protecting group such as tert-butyl group, followed, if desired, by the conversion of the group
• reaction is carried out in an aprotic solvent such as halohydrocarbon e.g. dichloromethane, chlorobenzene or acetonitrile at low temperature e.g. -78°C in the presence of a Lewis acid such as zinc bromide and zinc chloride.
• aprotic solvent such as halohydrocarbon e.g. dichloromethane, chlorobenzene or acetonitrile
• the conversion of the group NH into the nitrogen protected group NR 3 may be obtained using conventional means for introducing such nitrogen protecting groups, e.g. reaction with the group R 3 X wherein X is a leaving group e.g. halogen or methanesulphonate.
• the process for preparing compounds of formulae (II) or (IV), using the intermediate (V) when prepared from intermediates (VI) and (VII), is novel and forms a further feature of the invention.
• a particularly preferred embodiment of this novel process for preparing compounds of formula (V) is to use an intermediate ester (VI), wherein R 6 group is derived from (+)R t-butyl lactate alcohol. This yields a mixture of diastereomeric esters in which the required diastereomeric ester is obtained in diastereomeric excess.
• the reaction is preferably carried out in a solvent such as an aromatic hydrocarbon (e.g. benzene toluene or xylene) at a temperature ranging from ambient to the reflux temperature of the reaction mixture.
• a solvent such as an aromatic hydrocarbon (e.g. benzene toluene or xylene) at a temperature ranging from ambient to the reflux temperature of the reaction mixture.
• the carboxylic acids protecting group may be removed by conventional procedures known for removing such groups.
• is a benzyl group
• this may be removed by hydrolysis using an alkali metal hydroxide e.g. lithium hydroxide or sodium hydroxide in a suitable solvent such as ethanol or isopropanol, water or mixtures thereof, followed, where desired or necessary, by that addition of a suitable acid e.g. hydrochloric acid to give the corresponding free carboxylic acid.
• R 4 is a t butyl group this may be removed by hydrolysis using organic acids e.g. formic acid.
• the nitrogen protecting group may be removed by conventional procedures known for removing such groups, for example by acid or base hydrolysis.
• R 3 is alkoxycarbonyl e.g. t-butoxycarbonyl or phenylsulphonyl it may be removed by alkaline hydrolysis using for example lithium hydroxide in a suitable solvent such as tetrahydrofuran or an alkanol e.g. isopropanol.
• the alkoxycarbonyl group may be removed by acid hydrolysis.
• Physiologically acceptable salts of compound I may be prepared by treating the corresponding acid with an appropriate base in a suitable solvent.
• alkali and alkaline metal salts may be prepared from an alkali or alkaline metal hydroxide, or the corresponding carbonate, bicarbonate or thalkylsilanolate e.g. trimethylsiianolate thereof.
• alkali or alkaline earth salts may be prepared by direct hydrolysis of carboxylic acid protected derivatives of compound I with the appropriate alkali or alkaline metal hydroxide.
• EA ethyl acetate
• CH cyclohexane
• DCM dichloromethane
• THF tetrahydrofuran
• TFA trifluoroacetic acid
• TEA triethylamine
• DMSO dimethylsulphoxide
• Tic refers to thin layer chromatography on silica plates. Solution were dried over anhydrous sodium sulphate; r.t. (RT) refers to room temperature.
• Lithium hydroxide monohydrate (12.84mg) was added to a solution of diastereoisomer 1a (from Example 1 86mg) in tetrahydrofuran (5ml) and water (2.5ml). The solution was stirred at 23°C for 30 minutes, then concentrated in vacuo. The residue was diluted with further water (10ml) and extracted with ethyl acetate (2X15ml).
• the affinity of the compound of the invention for strychnine insensitive glycine binding site located on the NMDA receptor complex was determined using the procedure of Kishimoto H. et al J. Neurochem 1981 , 37, 1015-1024. The pKi value obtained is 8.8.

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• 1997
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  • 1998-03-24 HU HU0001661A patent/HUP0001661A3/hu unknown
  • 1998-03-24 AU AU72094/98A patent/AU731394B2/en not_active Ceased
  • 1998-03-24 TR TR1999/02315T patent/TR199902315T2/xx unknown
  • 1998-03-24 EA EA199900755A patent/EA199900755A1/ru unknown
  • 1998-03-24 BR BR9808424-0A patent/BR9808424A/pt not_active IP Right Cessation
  • 1998-03-24 AP APAP/P/1999/001659A patent/AP9901659A0/en unknown
• 1999
  • 1999-09-17 IS IS5186A patent/IS5186A/is unknown
  • 1999-09-24 NO NO994679A patent/NO994679L/no not_active Application Discontinuation

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