Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention is concerned with the sodium salt of the excitatory amino acid antagonist (E) 4,6-dichloro-3-(2-oxo-1-phenylpyrrolidin-3-yledine methyl)- 1 H-indole-2-carboxylic acid, its production, isolation and use in therapy.
• E excitatory amino acid antagonist 4,6-dichloro-3-(2-oxo-1-phenylpyrrolidin-3-yledine methyl)- 1 H-indole-2-carboxylic acid
• WO 95/1057 describes inter alia the compound of formula (1).
• the compound of formula (I) and salts thereof e.g. the sodium salt are useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases.
• the compounds are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia cardiac arrest.
• the compounds are 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. They have further uses in the treatment or prevention of status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodengeration , (e.g. AIDS, encephalopaties), Down's syndrome, epilepsy, schizophrenia, depression, anxiety, pain, migraine, neurogenic bladder, irritative bladder disturbances, drug dependency, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine, benzodiazepine, and emesis.
• status epilecticus contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodengeration , (e.g. AIDS, encephalopaties), Down's syndrome, epilepsy, schizophrenia, depression, anxiety, pain, migraine, neurogenic bladder, irritative bladder disturbance
• the sodium salt of the compound of formula (I) is of particular importance since it enables the compound to be conveniently formulated for administration to the patients. There is thus a need to produce the sodium salt of the compound of formula (I) in as pure and as highly crystalline a condition as possible in order to fulfil the exacting standards required for a pharmaceutical product.
• the process by which the sodium salt of the compound of formula (I) also needs to be one which is convenient to carry out on a plant scale, and from which the product can be readily isolated.
• the sodium salt of the compound of formula (I) has been prepared and isolated in solid form by lyophilisation of an aqueous solution of the sodium salt of a compound of formula (I) as described in WO 95/1057. This process is not particularly convenient for use on a plant scale and the product thus obtained is not the highly crystalline product desired.
• the sodium salt of the compound of formula (I) can be advantageously prepared and isolated in a crystalline hydrated form which hydrated form can be readily obtained with the requred high degree of purity and good stability and thus fulfils the exacting criteria required for a pharmaceutical product.
• the present invention thus provides a new crystalline hydrated form of the sodium salt of the compound of formula (I). More particularly the invention provides a crystalline hydrate which by analysis contains from 2.5 to 3.1 % water by weight, and preferably 2.6 to 2.9% water by weight e.g. 2.6 to 2.8%.
• the water content given above for the new crystalline hydrated form is that for the product which has been effectively dried to constant weight; for example dried under vacuum (1 to 5 mm Hg) at 40-45°C for up to 4 days.
• the crystalline hydrated form of the sodium salt of the compound of formula (I) may be characterised by its infra red spectrum as a mull in mineral oil, and or its X-ray powder diffraction pattern.
• the invention thus provides a crystalline hydrated form of the sodium salt of the compound of formula (1) characterised by an infra-red spectrum as a mull in mineral oil and with KBr discs showing the following peaks:
• the invention also provides a crystalline hydrated form of the sodium salt of the compound of formula I characterised by the following - X-ray powder diffraction pattern expressed as 2 Theta (1 ⁇ ) values and obtained on a Philips X 1 Part MPD Theta-2 Theta diffractometer utilising CuK ⁇ radiation (1.541 angstroms) with a step size of 0.04°/sec and count time of 1 sec.
• a further aspect of the invention provides a process for the preparation of the new crystalline hydrated form of the sodium of the compound of formula (I) by crystallisation from a mixture of an alkanol (e.g. ethanol, IMS (ethanol/methanol 95/5) or isopropanol) and water.
• an alkanol e.g. ethanol, IMS (ethanol/methanol 95/5) or isopropanol
• the crystallisation process is carried out at a temperature between 55° and reflux and conveniently 60-80°C.
• the acid may be dissolved with heating in the alkanol e.g. isopropanol or IMS containing aqueous sodium hydroxide solution. If necessary, the hot solution may then diluted with water to effect crystallisation and then cooled.
• alkanol e.g. isopropanol or IMS containing aqueous sodium hydroxide solution.
• the hot solution may then diluted with water to effect crystallisation and then cooled.
• the new crystalline hydrated form of the sodium salt of the compound formula (I) may be prepared and isolated directly by the hydrolysis of an alkyl ester e.g. C ⁇ _4alkyl ester such as the methyl or ethyl ester of the compound of formula (I) by heating with aqueous sodium hydroxide and an alkanol e.g. ethanol, IMS (ethanol/methanol 95/5) or isopropanol, followed if necessary by addition of water.
• an alkyl ester e.g. C ⁇ _4alkyl ester
• an alkanol e.g. ethanol, IMS (ethanol/methanol 95/5) or isopropanol
• the alkyl ester of the compound of formula (I) may be prepared by reaction of the corresponding alkyl ester of 3-formyl-4,6-dichloroindole-2- carboxylic acid with tributyl (2-oxo-1-phenylpyrrolin-1-yl)phosphonium bromide in a solvent such as an alkanol e.g. ispropanol and in the presence of a base e.g. 1 ,8-diazabicyclo[5.4.0]undec-7-ene.
• a solvent such as an alkanol e.g. ispropanol
• a base e.g. 1 ,8-diazabicyclo[5.4.0]undec-7-ene.
• the invention also provides for the use of the new crystalline hydrated form of the sodium salt of compound of formula (I) 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 the new crystalline hydrated form of the sodium salt of compound of formula (I) 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 the new crystalline hydrated form of the sodium salt of the compound of formula (I).
• the inventon provides a method for the treatment or prevention of pain which comprises administering to a patient in need thereof an effective amount of the new crystalline hydrated form of the sodium salt of the compound of formula (I).
• 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- 100mg preferably 60-80mg per day.
• a daily dose will typically be within the range 100-800mg e.g. 200-600mg 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.
• the compound of the invention 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 the new crystalline hydrated form of the sodium salt of the compound of formula (I) together with one or more pharmaceutically acceptable carriers therefor 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.
• Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, accacia, gelatin, 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
• compositions may take the form of tablets or lozenges formulated in conventional manner.
• the 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.
• the compound 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 propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser.
• a suitable propellant such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser.
• a suitable propellant such as dichlorod
• the compound 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.
• the 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 compound of formula (I) or an alkyl ester thereof may be prepared according to the processes described in WO95/1057.
• an alkyl ester of the compound of formula (I) may be prepared by the process more specifically described herein in the Examples.
• N,N,N 1 N 1 -Tetramethylethylene diamine (23.3ml) was added to a solution of N- phenylpyrrolidinone (5g) in dichloromethane (50ml). The solution was cooled to 0-5° and trimethylsilyl triflate (8.4ml) was added over ca 20 mins maintaining the temperature in the range 0-5°. The resultant solution was stirred for 10 mins and a solution of pyridinium bromide perbromide (13g) in acetonitrile (20ml) was added over ca 20 mins maintaining the temperature in the range 0-10°. The resultant suspension was stirred at 0-5° for ca 60 mins.
• Aqueous sodium bicarbonate solution (50ml) was added, cautiously. The mixture was stirred for ca 5 mins and the layers are separated. The aqueous phase was diluted with water (20ml) and back extracted with dichloromethane (20ml). The combined organic phases were washed with further sodium bicarbonate solution (50ml), 2M hydrochloric acid (2x50ml) and water (50ml), back extracting each wash with dichloromethane (10ml). The organic solution was dried (MgS04) and concentrated on a rotavapor.
• Ethyl (E)-4,6-dichloro-3-(2-oxo-1 -phenyl-pyrrolidin-3-ylidenemethyl)-1 H-indole-2- carboxylate (494g) was added slowly, without stirring, to a two phase system composed of isopropanol (3458ml) and NaOH 32%w/w (640ml). The reaction mixture was heated to reflux (in 1 hr 20min) and stirred for 1.5hrs. Water (10374ml) was added dropwise in 24 minutes (final temp. 55°C).
• reaction mixture was stirred for 30min at 55/59°C, cooled to 15°C in 2hrs 15min then the reaction mixture was stirred for 45min, filtered (on a 27cm diameter teflon filter with polypropylene as support). And washed with a mixture of isopropanol/water 1/3 (988ml) and water (5928ml). The resulting solid was dried under vacuum at 40 °C for 22hrs 15min to give the title compound .(475g) Water content 2.66% by weight.
• the tablets may be manufactured using a standard dry blending and direct compression process followed by a conventional film coating and optionally followed by an enteric coating.
• the active ingredient is the compound of Example 1 and the amount is equivalent to 5 to 100mg of the parent free acid.
• Suitable conventional film coats include Opadry white and suitable enteric coatings include Sureteric Opadry enteric white.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Biomedical Technology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Neurology (AREA)
• Veterinary Medicine (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pyrrole Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Indole Compounds (AREA)

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• 1997
  • 1997-03-05 GB GBGB9704498.6A patent/GB9704498D0/en active Pending
• 1998
  • 1998-03-03 IL IL13148998A patent/IL131489A0/xx unknown
  • 1998-03-03 EP EP98913613A patent/EP0966463A1/en not_active Withdrawn
  • 1998-03-03 WO PCT/EP1998/001146 patent/WO1998039327A1/en not_active Application Discontinuation
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  • 1998-03-03 JP JP53813598A patent/JP2001513796A/ja active Pending
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  • 1998-03-03 CN CN98803053A patent/CN1249750A/zh active Pending
  • 1998-03-03 PE PE1998000149A patent/PE51399A1/es not_active Application Discontinuation
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  • 1998-03-03 BR BR9808305-8A patent/BR9808305A/pt not_active Application Discontinuation
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• 1999
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  • 1999-09-03 NO NO994303A patent/NO994303L/no not_active Application Discontinuation
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