+

WO1998042673A1 - Derive d'acide quinoleine-2-carboxylique et son utilisation en tant qu'antagoniste d'acides amines excitateurs - Google Patents

Derive d'acide quinoleine-2-carboxylique et son utilisation en tant qu'antagoniste d'acides amines excitateurs Download PDF

Info

Publication number
WO1998042673A1
WO1998042673A1 PCT/EP1998/001700 EP9801700W WO9842673A1 WO 1998042673 A1 WO1998042673 A1 WO 1998042673A1 EP 9801700 W EP9801700 W EP 9801700W WO 9842673 A1 WO9842673 A1 WO 9842673A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
carboxylic acid
protecting group
formula
group
Prior art date
Application number
PCT/EP1998/001700
Other languages
English (en)
Inventor
Romano Di Fabio
Barbara Bertani
Giuseppe Alvaro
Original Assignee
Glaxo Wellcome S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA002284710A priority Critical patent/CA2284710A1/fr
Priority to BR9808424-0A priority patent/BR9808424A/pt
Priority to JP54323498A priority patent/JP2001518901A/ja
Priority to IL13191998A priority patent/IL131919A0/xx
Priority to EA199900755A priority patent/EA199900755A1/ru
Priority to HU0001661A priority patent/HUP0001661A3/hu
Priority to NZ337793A priority patent/NZ337793A/en
Priority to KR1019997008630A priority patent/KR20010005567A/ko
Application filed by Glaxo Wellcome S.P.A. filed Critical Glaxo Wellcome S.P.A.
Priority to AU72094/98A priority patent/AU731394B2/en
Priority to APAP/P/1999/001659A priority patent/AP9901659A0/en
Priority to EP98919133A priority patent/EP0971896A1/fr
Priority to PL98335865A priority patent/PL335865A1/xx
Publication of WO1998042673A1 publication Critical patent/WO1998042673A1/fr
Priority to IS5186A priority patent/IS5186A/is
Priority to NO994679A priority patent/NO994679L/no

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

Enantiomère (+) d'acide E 4-(4-acétylamino-phénylcarbamoyl-méthylène)-5,7-dichloro-1,2,3,4-tétrahydroquinoléine 2-carboxylique et ses sels antagonistes d'acides aminés excitateurs, procédés servant à les préparer, compositions pharmaceutiques les contenant et leur utilisation en médecine.
PCT/EP1998/001700 1997-03-26 1998-03-24 Derive d'acide quinoleine-2-carboxylique et son utilisation en tant qu'antagoniste d'acides amines excitateurs WO1998042673A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
NZ337793A NZ337793A (en) 1997-03-26 1998-03-24 Quinoline-2-carboxylic acid derivatives and the use of these derivatives in the preparation of medicaments for antagonising the effect of excitatory amino acids upon the NMDA receptor complex
JP54323498A JP2001518901A (ja) 1997-03-26 1998-03-24 キノリン−２−カルボン酸誘導体およびその興奮性アミノ酸拮抗薬としての使用
IL13191998A IL131919A0 (en) 1997-03-26 1998-03-24 Quinoline-2-carboxylic acid derivative and its use as excitatory amino acids antagonist
EA199900755A EA199900755A1 (ru) 1997-03-26 1998-03-24 Производное хинолин-2-карбоновой кислоты и его применение в качестве антагониста возбуждающих аминокислот
HU0001661A HUP0001661A3 (en) 1997-03-26 1998-03-24 Quinoline-2-carboxylic acid derivative and its use as excitatory amino acids antagonist
KR1019997008630A KR20010005567A (ko) 1997-03-26 1998-03-24 퀴놀린-2-카르복실산 유도체 및 그의 흥분성 아미노산 길항제로서의 용도
AU72094/98A AU731394B2 (en) 1997-03-26 1998-03-24 Quinoline-2-carboxylic acid derivative and its use as excitatory amino acids antagonist
CA002284710A CA2284710A1 (fr) 1997-03-26 1998-03-24 Derive d'acide quinoleine-2-carboxylique et son utilisation en tant qu'antagoniste d'acides amines excitateurs
BR9808424-0A BR9808424A (pt) 1997-03-26 1998-03-24 Composto, processos para a preparação do mesmo, para a preparação dos intermediários e para tratamento de um mamìfero, incluindo o ser humano, composição farmacêutica, e, uso de um composto.
APAP/P/1999/001659A AP9901659A0 (en) 1997-03-26 1998-03-24 Quinoline-2-carboxylic acid derivatives and its use as excitatory amino acids antagonist.
EP98919133A EP0971896A1 (fr) 1997-03-26 1998-03-24 Derive d'acide quinoleine-2-carboxylique et son utilisation en tant qu'antagoniste d'acides amines excitateurs
PL98335865A PL335865A1 (en) 1997-03-26 1998-03-24 Derivative of quinoline-2-carboxylic acid and application thereof as an antagonist of stimulating amino acids
IS5186A IS5186A (is) 1997-03-26 1999-09-17 Kínólín-2-karboxýlsýru afleiða og notkun hennar sem mótlyf fyrir örvandi amínósýrur
NO994679A NO994679L (no) 1997-03-26 1999-09-24 Quinolin-2-karboksylsyrederivat og anvendelse derav som eksitatorisk aminosyreantagonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9706294.7A GB9706294D0 (en) 1997-03-26 1997-03-26 Heterocyclic compound
GB9706294.7 1997-03-26

Publications (1)

Publication Number Publication Date
WO1998042673A1 true WO1998042673A1 (fr) 1998-10-01

Family

ID=10809909

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/001700 WO1998042673A1 (fr) 1997-03-26 1998-03-24 Derive d'acide quinoleine-2-carboxylique et son utilisation en tant qu'antagoniste d'acides amines excitateurs

Country Status (20)

Country Link
EP (1) EP0971896A1 (fr)
JP (1) JP2001518901A (fr)
KR (1) KR20010005567A (fr)
CN (1) CN1257482A (fr)
AP (1) AP9901659A0 (fr)
AU (1) AU731394B2 (fr)
BR (1) BR9808424A (fr)
CA (1) CA2284710A1 (fr)
EA (1) EA199900755A1 (fr)
GB (1) GB9706294D0 (fr)
HU (1) HUP0001661A3 (fr)
ID (1) ID24306A (fr)
IL (1) IL131919A0 (fr)
IS (1) IS5186A (fr)
NO (1) NO994679L (fr)
NZ (1) NZ337793A (fr)
PL (1) PL335865A1 (fr)
TR (1) TR199902315T2 (fr)
WO (1) WO1998042673A1 (fr)
YU (1) YU47699A (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003505512A (ja) * 1999-07-29 2003-02-12 インペリアル カレッジ オブ サイエンス， テクノロジー アンド メディシン Ｎｍｄａアンタゴニストとしてのキセノン
WO2003014124A1 (fr) * 2001-08-03 2003-02-20 Grünenthal GmbH Derives d'acide 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo'c!fluorene-6-carboxylique substitues comme antagonistes nmda
WO2004071381A3 (fr) * 2003-02-13 2004-11-18 Gruenenthal Gmbh Medicaments contenant des composes acide 2-arylaminoacetique substitue et/ou des composes acide 2-heteroarylaminoacetique substitue
US6956055B2 (en) 2001-07-05 2005-10-18 Grunenthal Gmbh Substituted γ-lactone compounds as NMDA-antagonists
WO2007010383A1 (fr) 2005-07-22 2007-01-25 Mochida Pharmaceutical Co., Ltd. Nouveau dérivé d'acétamide d'hétérocyclidène
RU2451014C2 (ru) * 2005-07-22 2012-05-20 Мотида Фармасьютикал Ко., Лтд. Новое производное гетероциклиден ацетамида
WO2014011590A2 (fr) 2012-07-12 2014-01-16 Javitt Daniel C Composition et méthode pour le traitement de la dépression et de la psychose chez l'homme
WO2018229744A1 (fr) 2017-06-12 2018-12-20 Glytech Llc. Traitement de la dépression avec des antagonistes du nmda et de la d2/5ht2a ou des antagonistes de la 5ht2a sélectifs

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4360891B2 (ja) 2003-12-09 2009-11-11 アルパイン株式会社 放送受信機能を備えた電子装置およびその装置における電子番組ガイドの表示方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0386839A2 (fr) * 1989-03-08 1990-09-12 Merck Sharp & Dohme Ltd. Dérivés de tétrahydroquinoléine utiles pour les affections neurodégénératives
WO1997012870A1 (fr) * 1995-09-29 1997-04-10 Glaxo Wellcome S.P.A. Tetrahydroquinolines utiles en tant qu'antagonistes du nmda (n-methyl-d-aspartate)
WO1998007704A1 (fr) * 1996-08-17 1998-02-26 Glaxo Wellcome S.P.A. Derives de la tetrahydroquinoline utilises comme antagonistes d'eaa

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0386839A2 (fr) * 1989-03-08 1990-09-12 Merck Sharp & Dohme Ltd. Dérivés de tétrahydroquinoléine utiles pour les affections neurodégénératives
WO1997012870A1 (fr) * 1995-09-29 1997-04-10 Glaxo Wellcome S.P.A. Tetrahydroquinolines utiles en tant qu'antagonistes du nmda (n-methyl-d-aspartate)
WO1998007704A1 (fr) * 1996-08-17 1998-02-26 Glaxo Wellcome S.P.A. Derives de la tetrahydroquinoline utilises comme antagonistes d'eaa

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRANDSTADTER S M ET AL.: "Reactions of ketene silyl acetals with imine-complexes of titanium tetrachloride. New and convenient route to 5,6-dihydro-2-pyridones and 5-amino-2-alkenoates", TETRAHEDRON LETTERS, vol. 28, no. 6, 1987, Oxford, GB, pages 613 - 6, XP002074162 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003505512A (ja) * 1999-07-29 2003-02-12 インペリアル カレッジ オブ サイエンス， テクノロジー アンド メディシン Ｎｍｄａアンタゴニストとしてのキセノン
US6956055B2 (en) 2001-07-05 2005-10-18 Grunenthal Gmbh Substituted γ-lactone compounds as NMDA-antagonists
WO2003014124A1 (fr) * 2001-08-03 2003-02-20 Grünenthal GmbH Derives d'acide 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo'c!fluorene-6-carboxylique substitues comme antagonistes nmda
DE10137487A1 (de) * 2001-08-03 2003-03-27 Gruenenthal Gmbh Substituierte 5,6,6a,11b-Tetrahydro-7-oxa-6-aza- benzo[c]fluoren-6-carbonsäurederivate
US7199130B2 (en) 2001-08-03 2007-04-03 Gruenenthal Gmbh Substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds as NMDA-antagonists
US7432296B2 (en) 2003-02-13 2008-10-07 Gruenenthal Gmbh Pharmaceutical formulations containing substituted 2-aryl-aminoacetic acid compounds and/or substituted 2-heteroaryl-aminoacetic acid compounds
WO2004071381A3 (fr) * 2003-02-13 2004-11-18 Gruenenthal Gmbh Medicaments contenant des composes acide 2-arylaminoacetique substitue et/ou des composes acide 2-heteroarylaminoacetique substitue
EP1908753A4 (fr) * 2005-07-22 2009-11-11 Mochida Pharm Co Ltd Nouveau dérivé d'acétamide d'hétérocyclidène
WO2007010383A1 (fr) 2005-07-22 2007-01-25 Mochida Pharmaceutical Co., Ltd. Nouveau dérivé d'acétamide d'hétérocyclidène
US7910751B2 (en) 2005-07-22 2011-03-22 Mochida Pharmaceutical Co., Ltd. Heterocyclidene acetamide derivative
AU2006271297B2 (en) * 2005-07-22 2012-02-02 Mochida Pharmaceutical Co., Ltd. Novel heterocyclidene acetamide derivative
RU2451014C2 (ru) * 2005-07-22 2012-05-20 Мотида Фармасьютикал Ко., Лтд. Новое производное гетероциклиден ацетамида
AU2006271297C1 (en) * 2005-07-22 2012-06-14 Mochida Pharmaceutical Co., Ltd. Novel heterocyclidene acetamide derivative
US8383839B2 (en) 2005-07-22 2013-02-26 Mochida Pharmaceutical Co., Ltd. Heterocyclidene acetamide derivative
NO341962B1 (no) * 2005-07-22 2018-03-05 Mochida Pharm Co Ltd Nytt heterocyklidenacetamidderivat
WO2014011590A2 (fr) 2012-07-12 2014-01-16 Javitt Daniel C Composition et méthode pour le traitement de la dépression et de la psychose chez l'homme
EP3263108A1 (fr) 2012-07-12 2018-01-03 Glytech LLC Composition et procédé de traitement de la dépression et de psychoses chez les humains
WO2018229744A1 (fr) 2017-06-12 2018-12-20 Glytech Llc. Traitement de la dépression avec des antagonistes du nmda et de la d2/5ht2a ou des antagonistes de la 5ht2a sélectifs

Also Published As

Publication number Publication date
YU47699A (sh) 2001-12-26
EP0971896A1 (fr) 2000-01-19
GB9706294D0 (en) 1997-05-14
BR9808424A (pt) 2000-05-23
AU7209498A (en) 1998-10-20
JP2001518901A (ja) 2001-10-16
CA2284710A1 (fr) 1998-10-01
IL131919A0 (en) 2001-03-19
HUP0001661A2 (hu) 2000-09-28
NO994679L (no) 1999-11-24
TR199902315T2 (xx) 2000-05-22
KR20010005567A (ko) 2001-01-15
EA199900755A1 (ru) 2000-08-28
NO994679D0 (no) 1999-09-24
ID24306A (id) 2000-07-13
IS5186A (is) 1999-09-17
AP9901659A0 (en) 1999-09-30
CN1257482A (zh) 2000-06-21
HUP0001661A3 (en) 2001-12-28
PL335865A1 (en) 2000-05-22
AU731394B2 (en) 2001-03-29
NZ337793A (en) 2001-02-23

Similar Documents

Publication Publication Date Title
US5374648A (en) Indole derivatives and pharmaceutical use thereof
US5686461A (en) Indole derivatives
AP877A (en) Tetrahydroquinoline derivatives as EAA antagonists.
US5919811A (en) 3-Substituted-indole-2-carboxylic acid derivatives as excitatory amino acid antagonists
US5977136A (en) Tetrahydroquinolines as NMDA antagonists
AU731394B2 (en) Quinoline-2-carboxylic acid derivative and its use as excitatory amino acids antagonist
US20020052391A1 (en) Tetrahydroquinoline derivatives as glycine antagonists
US6713491B2 (en) Heterocyclic derivatives
MXPA99008720A (en) Quinoline-2-carboxylic acid derivative and its use as excitatory amino acids antagonist
CZ340599A3 (cs) Derivát kyseliny chinolin-2-karboxylové

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 131919

Country of ref document: IL

Ref document number: P-476/99

Country of ref document: YU

Ref document number: 98805302.0

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 337793

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 72094/98

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 199900755

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 1019997008630

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2284710

Country of ref document: CA

Ref document number: 2284710

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/1999/008720

Country of ref document: MX

Ref document number: 1998919133

Country of ref document: EP

Ref document number: 1999/02315

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: PV1999-3405

Country of ref document: CZ

ENP Entry into the national phase

Ref document number: 1998 543234

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 09381300

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1998919133

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV1999-3405

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019997008630

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 72094/98

Country of ref document: AU

WWR Wipo information: refused in national office

Ref document number: PV1999-3405

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1998919133

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1019997008630

Country of ref document: KR

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载