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WO2011015537A1 - Co-thérapie pour le traitement de l'épilepsie et des troubles associés - Google Patents

Co-thérapie pour le traitement de l'épilepsie et des troubles associés Download PDF

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Publication number
WO2011015537A1
WO2011015537A1 PCT/EP2010/061157 EP2010061157W WO2011015537A1 WO 2011015537 A1 WO2011015537 A1 WO 2011015537A1 EP 2010061157 W EP2010061157 W EP 2010061157W WO 2011015537 A1 WO2011015537 A1 WO 2011015537A1
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WO
WIPO (PCT)
Prior art keywords
methyl
oxy
phenyl
fluorophenyl
epilepsy
Prior art date
Application number
PCT/EP2010/061157
Other languages
English (en)
Inventor
Giuseppe Alvaro
Charles Large
Original Assignee
Glaxo Group Limited
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
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to EP10737076A priority Critical patent/EP2461807A1/fr
Priority to JP2012523303A priority patent/JP2013501026A/ja
Publication of WO2011015537A1 publication Critical patent/WO2011015537A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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 directed to co-therapy for the treatment of epilepsy and related disorders comprising administering to a subject in need thereof, co-therapy with a therapeutically effective amount of 5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)- prolinamide and a therapeutically effective amount of one or more anticonvulsant and / or anti-epileptic agents.
  • Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process.
  • Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy.
  • epilepsy Using a definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is estimated at approximately 0.3 to 0.5 percent in different populations throughout the world, with the prevalence of epilepsy estimated at 5 to 10 people per 1000.
  • Compound (5R)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof is useful in the treatment of epilepsy and related disorders.
  • the present invention is directed to a method for the treatment of epilepsy and related disorders comprising administering to a subject in need thereof, co-therapy with a therapeutically effective amount of one or more anticonvulsant or anti-epileptic agents and a therapeutically effective amount of (5R)-5-(4- ⁇ [(2- fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the subject to be treated is a human.
  • the present invention provides compound (5R)-5-(4- ⁇ [(2- fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more anticonvulsant and / or anti-epileptic agents for use in combination therapy in the treatment of epilepsy and related disorders .
  • the present invention provides the use of compound (5R)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more anticonvulsant and / or anti-epileptic agents for the treatment of epilepsy and related disorders in combination therapy.
  • the compound is (5R)-5-(4- ⁇ [(2- fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide hydrochloride.
  • the compound is (5R)-5-(4- ⁇ [(2- fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide hydrochloride.
  • the pharmaceutically acceptable salts of (5R)-5-(4- ⁇ [(2- fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
  • Examples include the HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.
  • suitable pharmaceutical salts see Berge et al, J.
  • prodrugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.
  • epilepsy and related disorders shall mean any disorder in which a subject (preferably a human adult, child or infant) experiences one or more seizures and / or tremors.
  • Suitable examples include, but are not limited to, epilepsy (including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like), seizures associated with Lennox- Gastaut syndrome, seizures as a complication of a disease or condition (such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, infection, and the like), essential tremor, restless limb syndrome, partial and generalised seizures (including tonic, clonic, tonic-clonic, atonic, myoclonic, absence seizures), secondarily generalized seizures, temporal lobe epilepsy, absence epilepsies (including childhood, juvenile, myoclonic, photo- and pattern-induced), severe epileptic encephalopathies (including hypoxia-related
  • the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor or restless limb syndrome, more preferably, the disorder is epilepsy (regardless of type, underlying cause or origin) or essential tremor.
  • subject refers to an animal, preferably a mammal, most preferably a human adult, child or infant, who has been the object of treatment, observation or experiment.
  • therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated; and / or reduction of the severity of one or more of the symptoms of the disease or disorder being treated.
  • therapeutically effective amount shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response.
  • the therapeutically effective amount of co-therapy comprising administration of (5/?)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and at least one suitable anti-epileptic agent
  • the amount of (5/?)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and/or the amount of the suitable anti- epileptic agent individually may or may not be therapeutically effective.
  • co-therapy shall mean treatment of a subject in need thereof by administering one or more anticonvulsant and / or anti-epileptic agent(s) and (5R)-5-(4- ⁇ [(2- fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein (5/?)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L- prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and the anticonvulsant and / or anti-epileptic agent(s) are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation.
  • the number of dosages administered per day for each compound may be the same or different.
  • (5/?)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and the anticonvulsant and / or anti-epileptic agent(s) may be administered via the same or different routes of administration.
  • suitable methods of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), intranasal, transdermal, and rectal.
  • Compounds may also be administered directly to the nervous system including, but not limited to, intracerebral, intraventricular, intracerebroventhcular, intrathecal, intracisternal, intraspinal and / or peri-spinal routes of administration by delivery via intracranial or intravertebral needles and / or catheters with or without pump devices.
  • (5R)-5-(4- ⁇ [(2- fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and the anticonvulsant and / or anti-epileptic agent(s) may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
  • antiepileptic agent and the abbreviation “AED” will be used interchangeably with the term “anticonvulsant agent,” and as used herein, refer to an agent capable of treating, inhibiting or preventing seizure activity or ictogenesis when the agent is administered to a subject or patient.
  • Suitable examples of anti-convulsant and / or anti-epileptic agents include, but are not limited to:
  • AMPA antagonists such as AMP-397, E-2007, NS-1209, talampanel, and the like;
  • Benzodiazepines such as diazepam, lorazepam, clonazepam, clobazam, and the like
  • Barbiturates such as phenobarbital, amobarbital, methylphenobarbital, primidone, and the like
  • Valproates such as valproic acid, valproate semisodium, valpromide, and the like;
  • GABA agents such as gabapentin, pregabalin, vigabatrin, losigamone, retigabine, rufinamide, SPD-421 (DP-VPA), T-2000, XP-13512, and the like;
  • lminostilbenes such as carbamazepine, oxcarbazepine, and the like
  • Hydantoins such as phenytoin sodium, mephenytoin, fosphenytoin sodium, and the like
  • NMDA antagonists such as harkoseramide, and the like
  • Sodium channel blockers such as BIA-2093, CO-102862, lamotrogine, and the like
  • Succinimides such as methsuximide, ethosuximide, and the like
  • AEDS such as acetazolamide, clomthiazole edisilate, zonisamide, felbamate, topiramate, tiagabine, levetiracetam, briveracetam, GSK-3621 15, GSK-406725, ICA-
  • CBD cannabis derivative isovaleramide (NPS-1776), RWJ-333369, safinamide, seletracetam, soretolide, stiripentol, valrocemide, and the like.
  • the anti-convulsant and / or anti-epileptic agent is selected from the group consisting of brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, safinamide, seletracetam, talampanel, tiagabine, topiramate, valproate, vigabatrin, zonisamide, benzodiazepines, barbiturates and sedative hypnotics.
  • the anti-convulsant and / or anti-epileptic agent(s) is selected from the group consisting of carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, talampanel, tiagabine, topiramate, valproate, vigabatrin and zonisamide.
  • the anti-convulsant and / or anti-epileptic agent(s) is selected from the group consisting of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate and zonisamide.
  • the anti-convulsant and / or anti-epileptic agent(s) is selected from the group consisting of carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, valproate and topiramate.
  • the anti-convulsant and / or anti-epileptic is selected from the group consisting of gabapentin, lamotrigine, levetiracetam, valproate and topiramate.
  • (5R)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more of the anticonvulsant and / or anti-epileptic agents may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the present invention provides methods of treating epilepsy and related disorders, regardless of underlying cause and stage of development, comprising administering to a subject in need thereof, co-therapy with a therapeutically effective amount of one or more anticonvulsant or anti-epileptic agents and a therapeutically effective amount of (5/?)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof as described herein.
  • the methods of this invention therefore provide the ability to suppress seizures, convulsions or the symptoms of an analogous seizure related disorder.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the invention provides pharmaceutical compositions comprising (5/?)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more anticonvulsant and / or anti-epileptic agents with a pharmaceutically acceptable carrier.
  • compositions containing (5R)-5-(4- ⁇ [(2- fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more anticonvulsant and / or anti-epileptic agents as the active ingredient can be prepared by intimately mixing the compound with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • 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 reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, for example from 10-60% by weight, of 5/?)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof, depending on the method of administration.
  • each unit will for example contain from 5-1000 mg of the active ingredient.
  • the dosage as employed for adult human treatment may range from 10 to 3000 mg per day depending on the route and frequency of administration.
  • a typical dose may be in the range of 50 to 1500 mg per day, for example 120 to 800 mg per day.
  • Therapeutically effective dosage levels and dosage regimens for the anti-convulsant and anti-epileptic agents disclosed herein may be readily determined by one of ordinary skill in the art.
  • therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example as listed on packaging labels, in standard dosage guidelines, in standard dosage references such as the Physician's Desk Reference (Medical Economics Company or online at http://vvwvv.pdrel.com) and other sources.
  • NMR spectra are typically recorded either on Varian instruments at 300, 400, 500 or 600 MHz, or on a Bruker instrument at 300 MHz and 400 MHz. Chemical shifts are reported in ppm ( ⁇ ) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to 9O 0 C. When more than one conformer was detected the chemical shifts for the most abundant one is reported.
  • SPE-SCX cartridges are ion exchange solid phase extraction columns by supplied by Varian.
  • the eluent used with SPE-SCX cartridges is methanol followed by 2N ammonia solution in methanol.
  • SPE-Si cartridges are silica solid phase extraction columns supplied by Varian.
  • XRPD X-Ray Powder Diffraction X Ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • n-Butyl lithium 1.6M solution in hexanes (0.88ml, 1.4mmol) was added dropwise to a solution of commercially available 1-bromo-4-[(phenylmethyl)oxy]benzene (390mg, 1.48mmol) in dry THF (2ml) at -78°C under nitrogen atmosphere.
  • the resulting suspension was stirred at -78°C for 40 minutes and then it was added dropwise to a solution of 1-(1 ,1-dimethylethyl) 2-methyl (2S)-5-oxo-1 ,2-pyrrolidinedicarboxylate (D1 , 300mg, 1.23mmol) in dry THF (2.4ml) previously cooled to -78°C.
  • the mixture was stirred at -78°C for 40 minutes and at -40 0 C for 1 h, then it was quenched at - 40 0 C with an aqueous saturated ammonium chloride solution.
  • the mixture was diluted with water and extracted with ethyl acetate.
  • Procedure 2 A stirred mixture of 4-bromophenol (19.22g, 1 11 mmol), orthofluorobenzyl bromide (2Og, 105.8mmol) and potassium carbonate (21.9g, 158.4mmol) in acetone (280ml) was heated at reflux for 6 hours. The reaction mixture was cooled to room temperature and filtered, washing the solid with TBME (40ml). The combined filtrate and washings were concentrated under vacuum to a final volume of about 40ml. The resulting solution was diluted with TBME (160ml) and washed with 1 M sodium hydroxide and brine, then concentrated under vacuum to an oil which slowly solidified to give the title compound (28.9g).
  • Procedure 1 To a stirred suspension of magnesium metal (9Og) in dry THF (60OmL) under a nitrogen atmosphere at room temperature was added iodine (0.3g). The mixture was heated to an internal temperature of 64 +/- 2°C. A solution of 1-[(4- bromophenoxy)methyl]-2-fluorobenzene (D1 1 ) (693g) in THF (150OmL) was added in two batches. Firstly 45 mL was added. Secondly, the remaining solution (1455 mL) was added dropwise. After addition, the reaction was heated at reflux for 1 h. The reaction mixture was cooled to room temperature.
  • This reaction mixture was then added slowly to a solution of commercially available 1-te/t-butyl 2-methyl (2S)-5- oxopyrrolidine-1 ,2-dicarboxylate (30Og) in THF (150OmL) cooled to -6O 0 C, maintaining the internal temperature below -60 0 C. The addition was completed in 2 hours. The reaction mixture was stirred for a further 15 minutes after addition, lsopropyl alcohol (30OmL) was then added dropwise whilst maintaining the temperature below -60 0 C. A mixture of aqueous saturated ammonium chloride solution/aqueous saturated sodium chloride solution (2/1 ; 90OmL) was added whilst maintaining the temperature at -50 0 C.
  • Procedure 2 A solution of methyl (2S)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-3,4- dihydro-2H-pyrrole-2-carboxylate (D13, 34g, 103.5mmol) in ethyl acetate (272ml) was placed in an autoclave and treated with trifluoroacetic acid (7.2ml). 5% Platinum on carbon catalyst (1.7g) was transferred as a slurry with ethyl acetate (68ml) and the reaction was stirred at room temperature under 50 psi hydrogen pressure for 5 hours.
  • Procedure 1 A solution of methyl (5/?)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L- prolinate (D14, 32.5g, 98.6mmol) in methanol (65ml) was cooled to 0-10 0 C. A solution of ammonia in methanol (ca 11.2M) was added in four portions over 11 hours (175.4ml, 43.8ml, 43.8ml. 43.8ml) then the reaction stirred at 15-20 0 C for 22 hours. Ammonia and methanol were removed under vacuum, then toluene (65ml) was added and the mixture heated to 60-65°C to give a solution, which was then concentrated under vacuum and the residue dried at 60 0 C.
  • Example 2 was also prepared as follows:
  • EtOAc (6ml) was added to (5R)-5-(4- ⁇ [(2-Fluorophenyl)methyl]oxy ⁇ phenyl)-L- prolinamide (E1 , 300 mg) and this was heated at 60 0 C for an hour to dissolve the compound. Then methanesulfonic acid (65 ⁇ l, 1.05 eq) was added to the solution and as soon as the acid was added, the solution went cloudy. This was then left to temperature cycle (0-40 0 C) for 2 days. The compound was isolated by filtration as a white solid, washed with EtOAc and dried in vacuo at 40 0 C overweek-end to afford 335 mg of the title compound.

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Abstract

La présente invention concerne la co-thérapie pour le traitement de l'épilepsie et des troubles associés. Ladite co-thérapie comporte l'administration, à un sujet en ayant besoin, d'une co-thérapie avec une quantité thérapeutique efficace de 5-(4-{[(2-fluorophényl)méthyl]oxy}phényl)-prolinamide, ou d'un sel ou d'un solvate de qualité pharmaceutique de celui-ci, et une quantité thérapeutique efficace d'un ou de plusieurs agents anti-convulsifs et/ou anti-épileptiques.
PCT/EP2010/061157 2009-08-05 2010-07-30 Co-thérapie pour le traitement de l'épilepsie et des troubles associés WO2011015537A1 (fr)

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EP10737076A EP2461807A1 (fr) 2009-08-05 2010-07-30 Co-thérapie pour le traitement de l'épilepsie et des troubles associés
JP2012523303A JP2013501026A (ja) 2009-08-05 2010-07-30 てんかん及び関連疾患の治療のための共治療法

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US23149809P 2009-08-05 2009-08-05
US61/231,498 2009-08-05

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