EP2461807A1

EP2461807A1 - Co-therapy for the treatment of epilepsy and related disorders

Info

Publication number: EP2461807A1
Application number: EP10737076A
Authority: EP
Inventors: Giuseppe Alvaro; Charles Large
Original assignee: Convergence Pharmaceuticals Ltd
Current assignee: Convergence Pharmaceuticals Ltd
Priority date: 2009-08-05
Filing date: 2010-07-30
Publication date: 2012-06-13
Also published as: WO2011015537A1; JP2013501026A; JP2016026163A

Abstract

The present invention relates 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, or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of one or more anticonvulsant and / or anti-epileptic agents.

Description

CO-THERAPY FOR THE TREATMENT OF EPILEPSY AND RELATED DISORDERS

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. 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.

20 to 30 % of epilepsy patients are refractory to current therapy.

Thus, there remains a need to provide an effective treatment for epilepsy and related disorders in cases where the patient is refractary to monotherapy.

Recently a patent application has been published as WO2007/042239, which describes compounds 5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-prolinamide of formula (I),

and pharmaceutically acceptable salts, solvates or prodrugs thereof.

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.

In one aspect, 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.

In one embodiment of the present invention, the subject to be treated is a human.

In another aspect, 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 . In a further aspect, 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. In one embodiment of the present invention, the compound is (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride. In one embodiment of the present invention, 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. For reviews on suitable pharmaceutical salts see Berge et al, J. Pharm, ScL, 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.

It will be appreciated by those skilled in the art that certain protected derivatives of [5R)- 5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All such prodrugs of compounds of the invention are included within the scope of the invention. Examples of suitable 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.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention.

As used herein, unless otherwise noted, the terms "epilepsy and related disorders" or "epilepsy or related disorder" 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 and Rasmussen's syndrome), febrile convulsions, epilepsy partialis continua, progressive myoclonus epilepsies (including Unverricht-Lundborg disease and Lafora's disease), post-traumatic seizures/epilepsy including those related to head injury, simple reflex epilepsies (including photosensive, somatosensory and proprioceptive, audiogenic and vestibular), metabolic disorders commonly associated with epilepsy such as pyridoxine-dependent epilepsy, Menkes' kinky hair disease, Krabbe's disease, epilepsy due to alcohol and drug abuse (e.g. cocaine), cortical malformations associated with epilepsy (e.g. double cortex syndrome or subcortical band heterotopia), chromosomal anomolies associated with seizures or epilepsy such as Partial monosomy (15Q) / Angelman syndrome)

and the like.

In one embodiment, 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.

The term "subject" as used herein, 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.

The term "therapeutically effective amount" as used herein, 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. Wherein the present invention is directed to co-therapy, adjunctive therapy or combination therapy, comprising administration of one or more compound(s) of formula (I) and one or more anticonvulsant or anti-epileptic agents, 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. For example, 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 would be the amount of (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and the amount of the suitable anti-epileptic agent that when taken together or sequentially have a combined effect that is therapeutically effective. Further, it will be recognized by one skilled in the art that in the case of co- therapy with a therapeutically effective amount, as in the example above, 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.

As used herein, the terms "co-therapy", "adjunctive therapy" and "combination 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. Where (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 in separate dosage forms, 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. Examples of 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.

As used herein, unless otherwise noted, the term "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:

(a) AMPA antagonists such as AMP-397, E-2007, NS-1209, talampanel, and the like;

(b) Benzodiazepines such as diazepam, lorazepam, clonazepam, clobazam, and the like; (c) Barbiturates such as phenobarbital, amobarbital, methylphenobarbital, primidone, and the like;

(d) Valproates such as valproic acid, valproate semisodium, valpromide, and the like; (e) GABA agents such as gabapentin, pregabalin, vigabatrin, losigamone, retigabine, rufinamide, SPD-421 (DP-VPA), T-2000, XP-13512, and the like;

(f) lminostilbenes such as carbamazepine, oxcarbazepine, and the like; (g) Hydantoins such as phenytoin sodium, mephenytoin, fosphenytoin sodium, and the like;

(h) NMDA antagonists such as harkoseramide, and the like; (i) Sodium channel blockers such as BIA-2093, CO-102862, lamotrogine, and the like; (j) Succinimides such as methsuximide, ethosuximide, and the like; and

(k) AEDS such as acetazolamide, clomthiazole edisilate, zonisamide, felbamate, topiramate, tiagabine, levetiracetam, briveracetam, GSK-3621 15, GSK-406725, ICA-

69673, CBD cannabis derivative, isovaleramide (NPS-1776), RWJ-333369, safinamide, seletracetam, soretolide, stiripentol, valrocemide, and the like.

In an embodiment, 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. In another embodiment, 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.

In another embodiment, the anti-convulsant and / or anti-epileptic agent(s) is selected from the group consisting of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate and zonisamide. In a further embodiment, 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.

In a still further embodiment, the anti-convulsant and / or anti-epileptic is selected from the group consisting of gabapentin, lamotrigine, levetiracetam, valproate and topiramate.

Advantageously, (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.

(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 may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical composition.

As used herein, the term "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.

According to a further aspect, 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. Pharmaceutical 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.

The pharmaceutical 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.

The 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. 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.

For parenteral administration, 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. In preparing solutions the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

(5/?)-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 as the raw chemical or in any of the foregoing compositions whenever treatment of epilepsy or related disorders is required.

The 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. Where the compositions comprise dosage units, 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. For oral 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. For example, 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. It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of (5/?)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide or a pharmaceutically acceptable salt, solvate or prodrug thereof and of one or more of the anticonvulsant and / or anti-epileptic agents will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

Experimentals

The invention is illustrated by the Examples described below.

In the procedures that follow, after each starting material, reference to a Description or Example by number is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

Where reference is made to the use of a "similar"procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variation, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions. The compounds described in the Examples described hereinafter have all been prepared as a first step from stereochemical^ pure methyl 5-oxo-L-prolinate or ethyl 5-oxo-D-prolinate, for example 99% ee. The stereochemistry of the compounds of the Descriptions and Examples have been assigned on the assumption that the pure configuration of 5-oxo-prolinate is maintained throughout any subsequent reaction conditions.

The absolute configuration of the stereocenter at the 2-position as shown below the has been assigned on the basis of NOE ¹H NMR experiments, by determining the relative stereochemistry of this stereocenter with respect to the one at the 5-position.

Compounds are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

Proton Magnetic Resonance (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 (δ) 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 9O⁰C. When more than one conformer was detected the chemical shifts for the most abundant one is reported. HPLC analysis indicated by R_t(HPLC): x min, was performed on an Agilent 1100 series instrument using a Luna 3u C18(2) 100A (50x2.0mm) column (mobile phase: 100% [water + 0.05% TFA] to 95% [acetonitrile + 0.05% TFA] in 8min, flux = 1 ml/min, detection wavelength 220nm. Mass spectra (MS) are typically taken on a 4 Il triple quadrupole Mass Spectrometer (Micromass UK) or on a Agilent MSD 1 100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode or on a Agilent LC/MSD 1 100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode coupled with HPLC instrument Agilent 1100 Series [LC/MS - ES (+):analysis performed on a Supelcosil ABZ +Plus (33x4.6 mm, 3μm) (mobile phase: 100% [water +0.1% HCO₂H] for 1 min, then from 100% [water +0.1% HCO₂H] to 5% [water +0.1% HCO₂H] and 95% [CH₃CN ] in 5 min, finally under these conditions for 2 min; T=40°C; flux= 1 mL/min; LC/MS - ES (-):analysis performed on a Supelcosil ABZ +Plus (33x4.6 mm, 3μm) (mobile phase: 100% [water +0.05% NH₃] for 1 min, then from 100% [water +0.05% NH₃ to 5% [water +0.05% NH₃] and 95% [CH₃CN ] in 5 min, finally under these conditions for 2 min; T=40°C; flux= 1 mL/min]. In the mass spectra only one peak in the molecular ion cluster is reported.

The optical rotation was measured on a JASCO DIP-360 digital polarimeter (λ=589nm, T=20°C, c=1 in MeOH). Flash silica gel chromatography are typically carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over Varian Mega Be-Si pre-packed cartridges or over pre-packed Biotage silica cartridges.

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.

In a number of preparation purification was performed using either Biotage manual flash chromatography (Flash+) or automatic flash chromatography (Horizon) systems. All these instruments work with Biotage Silica cartridge.

SPE-Si cartridges are silica solid phase extraction columns supplied by Varian.

It will be recognised that spectra and diffraction data will vary slightly according to various factors such as the temperature, concentration and instrumentation used. The skilled person will recognise that XRPD peak positions are affected by differences in sample height. The peak positions quoted herein are thus subject to a variation of +/- 0.15 degrees 2-theta. X-Ray Powder Diffraction X Ray Powder Diffraction (XRPD) analysis was performed on Bruker D5005, using SoI-X detector. The acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 5OmA, start angle: 2.0 °2Θ, end angle: 45.0 °2Θ, step size: 0.02 °2Θ , time per step: 1 seconds. The sample was prepared on zero background sample holder.

Differential Scanning Calorimetry (DSC): It should be recognized that the endotherm peak as measured is dependent under a number of factors including the machine employed, the rate of heating, the calibration standard, humidity and the purity of the sample used.

Melting points reported in the experimentals are estimated on the basis of the onset of endotherm peaks registered during DSC analysis. The following table lists the abbreviations used:

BOC2O bis(1 ,1-dimethylethyl) dicarbonate

DCM dichloromethane

DIPEA - diisopropylethylamine

DMAP - 4-(dimethylamino)pyridine

DMF dimethylformamide

O-(benzotriazol-1-yl)-N,N,N'N'-tetramethyluronium

TBTU tetrafluoroborate

THF tetrahydrofuran

TFA trifluoroacetic acid

MTBE methyl-f-butyl ether

Et20 Diethyl ether

AcOEt Ethyl acetate

MeOH Methyl alcohol

DMSO Dimethyl sulfoxide

Description 1 : 1-(1 ,1-dimethylethyl) 2-methyl (2S)-5-oxo-1 ,2-pyrrolidinedicarboxylate

D1 ):

To a solution of commercially available methyl 5-oxo-L-prolinate (2Og, 140mmol) in DCM (200ml) were added triethylamine (19.6ml, 140mmol), DMAP(17.2g, 140mmol) and then dropwise a solution of BOC₂O (61g, 280mmol) in DCM (100ml). The resulting red mixture was stirred at room temperature for 2 hours. Then the solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel eluting with cyclohexane / ethyl acetate (7:3 to 4:6) to afford (after a trituration in hexane / diethylether 1 :1 ) the title compound as a white solid (32.4g, 96%); Rf (cyclohexanes:ethyl acetate = 65:35): 0.21 ; ¹H NMR (300 MHz, CDCI₃) δ(ppm): 4.62 (dd, 1 H), 3.78 (s, 3H), 2.68-2.58 (m, 1 H), 2.52-2.45 (m, 1 H), 2.37-2.27 (m, 1 H), 2.08-1.97 (m, 1 H), 1.48 (s, 9H).

Description 2: methyl (2S)-2-({[(1 ,1-dimethylethyl)oxy1carbonyl)amino)-5-oxo-5-{4- [(phenylmethvDoxyiphenvDpentanoate (D2):

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 -40⁰C for 1 h, then it was quenched at - 40⁰C with an aqueous saturated ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure to give the crude material, which was purified by chromatography on silica gel eluting with cyclohexane / ethylacetate (95:5), thus affording the title compound as a white solid (170mg, 32%); Rf (cyclohexane:ethyl acetate = 8:2): 0.30; ¹HNMR (300 MHz, CDCI₃) δ(ppm): 7.95 (d, 2H), 7.50-7.33 (m, 5H), 7.03 (d, 2H), 5.20 (bs, 1 H), 5.15 (s, 2H), 4.45-4.35 (m, 1 H), 3.78 (s, 3H), 3.15-2.95 (m, 2H), 2.36-2.26 (m, 1 H), 2.16-2.02 (m, 1 H), 1.45 (s, 9H). Description 3: methyl (2S)-5-{4-[(phenylmethyl)oxy1phenyl)-3,4-dihvdro-2H-pyrrole-2- carboxylate (D3):

To a solution of methyl (2S)-2-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-5-oxo-5-{4- [(phenylmethyl)oxy]phenyl}pentanoate (D2, 323mg, 0.75mmol) in dry DCM (4ml) at 0⁰C, under nitrogen atmosphere was added trifluoroacetic acid (1 ml) dropwise. The resulting pale pink solution was allowed to warm to room temperature over 1 hour, then it was evaporated under reduced pressure, affording the title compound (D7, 291 mg, 0.68mmol, 91%) as a greenish oil which may be used in the next step without any further purification; R_t (HPLC): 3.69min; MS: (ES/+) m/z: 310 [MH⁺], C19H19NO3 requires 309.

Description 4: methyl (5/?)-5-{4-r(phenylmethyl)oxylphenyl)-L-prolinate (D4):

Description 5: methyl (5S)-5-{4-r(phenylmethyl)oxylphenyl)-L-prolinate (D5):

To a solution of methyl (2S)-5-{4-[(phenylmethyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole- 2-carboxylate (D3, 13.7g, 32.4mmol) in MeOH (200ml) was added PtO₂ (240mg) and the mixture was stirred under a hydrogen atmosphere (2 atmos) for 6 hours. Then the catalyst was filtered off and the solvent removed under reduced pressure to give a red oil which was dissolved in ethyl acetate and washed with NaHCO₃ solution. The resulting crude material was purified by chromatography on silica gel eluting with cyclohexane / ethyl acetate (9:1 to 8:2) to afford the title compounds: D4, 4.15g, 13.3mmol, Y=41%. MS: (ES/+) m/z: 312 [MH⁺]. C19H21 NO3 requires 31 1. Rt (HPLC): 3.80min. Rf (cyclohexane:ethyl acetate = 7:3): 0.18. ¹HNMR (300 MHz, CDCI₃) δ(ppm): 7.40 (d, 2H); 7.35 (t, 2H); 7.33 (d, 2H); 7.29 (t, 1 H); 6.93 (d, 2H); 5.03 (s, 2H); 4.23 (dd, 1 H); 4.00 (dd, 1 H); 3.71-3.79 (m, 3H); 2.18-2.30 (m, 1 H); 2.09-2.18 (m, 2H); 1.67-1.78 (m, 1 H). NOE between the proton at C2 and the proton at C5 could be observed.

D5, 0.6g, 1.9mmol, Y=6%. MS: (ES/+) m/z: 312 [MH⁺]. C19H21 NO3 requires 311 ; Rt (HPLC): 3.73min. Rf (cyclohexane:ethyl acetate = 7:3): 0.32. ¹HNMR (300 MHz, CDCI₃) δ(ppm): 7.40 (d, 2H); 7.35 (t, 2H); 7.29 (d, 2H); 7.28 (t, 1 H); 6.91 (d, 2H); 4.97-5.07 (m, 2H); 4.29 (dd, 1 H); 4.09 (dd, 1 H); 3.71-3.75 (m, 3H); 2.29-2.42 (m, 1 H); 2.09-2.20 (m, 1 H); 1.90-2.02 (m, 1 H); 1.69-1.82 (m, 1 H). NOE between the proton at C2 and the proton at C5 was not observed.

Description 6: (5/?)-5-{4-[(phenylmethyl)oxy]phenyl)-L-proline (D6):

Description 7j (5/?)-1 -{[(1 , 1 -dimethylethyl)oxy1carbonyl)-5-{4-

[(phenylmethvDoxyiphenvD-L-proline (D7):

To a solution of methyl (5/?)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate (D4, 120mg, 0.38mmol) in THF (2.3ml) was added LiOH monohydrate (26mg, 0.61 mmol) dissolved in water (1.1 ml), followed by methanol (1.1 ml). The resulting solution was stirred at room temperature for 2.5 hours, then left overnight at -18° C. Then the organic solvent was evaporated under reduced pressure maintaining the temperature at 38°C and the aqueous residue containing the acid intermediate (D6, Rt (HPLC) = 3.63min. MS: (ES/+) m/z: 298 [MH⁺]. C18H19NO3 requires 297) was treated with

BOC₂O (168mg, 0.77mmol) dissolved in THF (1.1 ml). The reaction mixture was stirred at room temperature for 3.5 hours. The organic solvent was evaporated and the basic aqueous solution was acidified at 0⁰C with aqueous 1 N HCI solution to pH=3, this acidic aqueous solution was extracted with ethyl acetate (2x1 OmI). The organic phase dried over Na₂SO₄ and evaporated under reduced pressure gave a solid, which was titurated in n-hexanes (3x6ml) affording the title compound as a white powder (D7, 137mg, 90% for two steps); Rt (HPLC): 5.81 min; Rf (cyclohexane:ethyl acetate = 1 :1 ): 0.34; MS: (ES/+) m/z: 420 [M+Na⁺] C23H27NO5 requires 397; MS: (ES/-) m/z: 396 [M-H] C23H27NO5 requires 397; ¹H NMR (300 MHz, CDCI₃) δ(ppm): 7.5-7.3 (m, 5H), 7.10 (bm, 2H), 6.90 (d, 2H), 5.08 (s, 2H), 4.65 (bm, 1 H), 4.50 (bm, 1 H), 2.58 (bm, 1 H), 2.31 (bm, 1 H), 2.1 1-1.90 (m, 2H), 1.16 (s, 9H).

Description 8j 1 ,1-dimethylethyl (2S,5/?)-2-(aminocarbonyl)-5-{4- r(phenylmethyl)oxylphenyl)-1-pyrrolidinecarboxylate (D8):

To a solution of (5/?)-1-{[(1 ,1-dimethylethyl)oxy]carbonyl}-5-{4-

[(phenylmethyl)oxy]phenyl}-L-proline (D7, 1.44g, 3.62mmol) in dry DMF (20ml) were added DIPEA (1.26ml, 7.24mmol), then TBTU (1.23g, 3.98mmol) and after 20 minutes, 1 ,1 ,1 ,3,3,3-hexamethyldisilazane (1.15ml, 5.43mmol). The reaction mixture was stirred at room temperature for 2h, then it was treated with aqueous 5% NaHCO₃ solution (30ml) and stirred for further 30 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed twice with brine/ice, dried over Na₂SO₄ and evaporated to give a colourless oil. This crude material was purified by chromatography on silica gel eluting with cyclohexane / ethyl acetate (7:3 to 5:5) to afford the title compound (1.25g, 87%); R^ (HPLC): 5.51 min; Rf (cyclohexane:ethyl acetate = 1 :1 ): 0.29. MS: (ES/+) m/z: 419 [M+Na⁺]; C23H28N2O4 requires 396. Description 9: 1 ,1-dimethylethyl (2S,5/?)-2-(aminocarbonyl)-5-(4-hvdroxyphenyl)-1- pyrrolidinecarboxylate (D9):

To a solution of 1 ,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-{4- [(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D8, 1.2g, 3.02mmol) in methanol (25ml) was added Pd/C 10% wt (210mg) and the mixture was stirred under hydrogen (1 atm) for 6 hours. The catalyst was filtered off and the solvent removed under reduced pressure to give the title compound as a white solid (870mg, 94%); R^ (HPLC): 3.61 min; Rf (cyclohexane:ethyl acetate = 1 :1 ): 0.18; MS: (ES/+) m/z: 329 [IvRNa⁺]. C16H22N2O4 requires 306; ¹H NMR (300 MHz, d₆-DMSO) δ ppm : 9.15 (bs, 1 H); 7.40 (bm, 2H); 7.30 (s, 1 H); 6.90 (s, 1 H); 6.65 (d, 2H); 4.50-4.80 (m, 1 H); 4.05-4.28 (m, 1 H); 2.07-2.24 (m, 1 H); 1.95-2.07 (m, 1 H); 1.60-1.89 (m, 2H); 1.00- 1.45 (m, 9H).

Description 10: 1 ,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-{[(2- fluorophenyl)rnetr)vHoxy)phenyl)-1-pyrrolidinecarboxylate (D10):

1-(Bromomethyl)-2-fluorobenzene (30μl, 0.220mmol) was added to a solution of 1 ,1- dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1 - pyrrolidinecarboxylate (D9, 45mg, 0.146mmol) and potassium carbonate (30mg, 0.217mmol) in acetonitrile (2ml). The mixture was stirred overnight at room temperature. After the reaction was finished, as shown by TLC, ethyl acetate and water were added. The organic phase was then washed with brine, dried (Na₂SO₄), filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane / ethyl acetate (7:3 to 6:4) to afford the title compound (51 mg, 85%); Rt (HPLC): 5.56 min; Rf (cyclohexane:ethyl acetate = 1 :1 ): 0.28; ¹H NMR (300 MHz, CDCI₃) δ(ppm): 7.56-7.48 (m, 1 H); 7.37-7.28 (m, 1 H); 7.24-7.06 (m, 5H); 6.93 (d, 2H); 5.45-5.37 (br. s, 1 H); 5.15 (s, 2H); 4.73-4.60 (m, 1 H); 4.53-4.45 (m, 1 H); 2.58-2.48 (m, 1 H); 2.34-2.25 (m, 1 H); 2.09-1.93 (m, 2H); 1.28-1.13 (br. s, 9H). Description 1 1 : 1-[(4-bromophenoxy)methyl1-2-fluorobenzene (D11 )

Procedure 1 : To a solution of 4-bromophenol (502.08g) dissolved in acetone (7322ml_) was added K₂CO₃ (57Og) and then benzylbromide (523g). The mixture was heated under reflux for 2hrs. The reaction mixture was then cooled at 25°C, filtered and the filter cake was washed with MTBE (1046ml_). The combined filtrate was concentrated to 100OmL and MTBE (4184ml_) were added. The mixture was washed with an aqueous 1 M NaOH solution (1464ml_), then with brine (130OmL) and the organic phase was concentrated to dryness. THF (130OmL) was added and the solvent was removed under reduced pressure to afford the title compound (902.1g); ¹H NMR (400 MHz, DMSO-d6) δ(ppm): 7.54 (td, 1 H); 7.46 (d, 2H); 7.42 (m, 1 H); 7.23 (m, 2H); 7.01 (d, 2H); 5.13 (s, 2H). D11 was also obtained as follows:

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).

1 H NMR (300 MHz, CHCI3-d). δ(ppm): 5.10 (s, 2H) , 6.86 (m, 2H) , 7.10 (m, 1 H) , 7.17 (m, 1 H) , 7.29 (m, 1 H) , 7.35 (m, 2H) , 7.38 (m, 1 H) .

Description 12: methyl (2S)-2-({r(1 ,1-dimethylethyl)oxy1carbonyl)amino)-5-(4-{r(2- fluorophenyl)methyl1oxy)phenyl)-5-oxopentanoate (D12)

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 -6O⁰C, maintaining the internal temperature below -60⁰C. 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 -60⁰C. A mixture of aqueous saturated ammonium chloride solution/aqueous saturated sodium chloride solution (2/1 ; 90OmL) was added whilst maintaining the temperature at -50⁰C. Water (600 mL) was added to dissolve the yellow precipitate. The organic phase was separated and was washed with aqueous 13% NaCI solution (60OmL). The organic phase was concentrated to dryness. EtOAc (150OmL) was then added and the solution was evaporated under reduced pressure to remove water. The residue was purified by chromatography on silica gel eluting with cyclohexane / ethyl acetate (90:10 to 8:2) to afford the title compound (287 g); ¹H NMR (600 MHz, DMSO-d6) δ(ppm): 7.93 (d, 2H); 7.57 (td, 1 H); 7.44 (m, 1 H); 7.27 (m, 3H); 7.14 (d, 2H); 5.24 (s, 2H); 4.04 (m, 1 H); 3.61 (s, 3H); 3.03 (m, 2H); 1.94 (m, 2H); 1.38 (s, 9H).

D12 was also obtained as follows:

Procedure 2: To a mixture of magnesium turnings (12.79g. 533mol), a trace of iodine and 1 ,2-dibromoethane in THF (86.ml)at 70-75°C, a solution of (4-bromophenyl (2- fluorophenyl)methyl ether) (D11 , 100g, 355.6mmol) in THF (216.25ml) was added over about 2 hours. The mixture was heated for a further 2 hours at 70-75°C then cooled to room temperature to give a solution of the Grignard reagent. A solution of 1 -(1 , 1 -dimethylethyl) 2-methyl (2S)-5-oxo-1 ,2-pyrrolidinedicarboxylate (43.25g, 177.8mmol) in THF (216.25ml) was cooled to -60°C and the solution of the Grignard reagent was added over 1 hour, then the mixture was stirred for 3 hours at -60⁰C. lsopropanol (43.25ml) was added dropwise, followed by saturated aqueous ammonium chloride (86.5ml) and brine (43.25ml), then the mixture warmed to room temperature. Water (173ml) and 50% acetic acid (50ml) to pH 6-7, followed by ethyl acetate (129.7ml). The layers were separated and the aqueous extracted with ethyl acetate (2 x 129.7ml). The combined organic layers were washed with brine then concentrated under vacuum. The residue was stirred with hexane (216.2ml), then the solid was filtered and washed with hexane. To the resulting solid, isopropanol (432.5ml) was added and the mixture stirred at 45°C for 15 minutes, then cooled to 5-10⁰C and stirred for 2 hours. The solid was filtered, washed with isopropanol and dried to give the title compound as a solid.

1 H NMR (300 MHz, CHCI3-d): δ(ppm): 1.42 (s, 9H); 2.04 (m, 1 H); 2.28 (m, 1 H); 3.03 (m, 2H); 3.74 (s, 3H); 4.37 (m, 1 H); 5.19 (b, 1 H); 5.20 (s, 2H); 7.02 (d, 2H); 7.1 1 (t, 1 H); 7.17 (t, 1 H); 7.33 (m, 1 H); 7.48 (t, 1 H); 7.94 (d, 2H).

Description 13: methyl (2S)-5-{4-r(2-fluorobenzyl)oxylphenyl)-3,4-dihvdro-2/-/-pyrrole- 2-carboxylate (D13)

Procedure 1 : To a solution of methyl (2S)-2-({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5- oxopentanoate (D12) (243g) in dry DCM (243OmL) at 0⁰C was added TFA (461 m L) dropwise. The mixture was allowed to warm to room temperature and stirred for 3hrs. Solvent and the excess TFA were removed under vacuum and the resulting dark oil was stripped with EtOAc (2 x 1215mL) and left overnight under a high vacuum. The title compound (392 g) was obtained as a red oil and used in the following step without any further purification; ¹H NMR (400 MHz, DMSO-d6) δ(ppm): 8.16 (m, 2H); 7.60 (td, 1 H); 7.46 (m, 1 H); 7.34 (m, 2H); 7.27 (m, 2H); 5.32 (s, 2H); 5.25 (m, 1 H); 3.77 (s, 3H); 3.57 (m, 2H); 2.60 (m, 1 H); 2.34 (m, 1 H).

D13 was also obtained as follows:

Procedure 2: A solution of methyl (2S)-2-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-5- (4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5-oxopentanoate (D12, 46g, 103mmol) in DCM (437ml) was treated dropwise with trifluoroacetic acid (87.4ml) at 0-5⁰C, then warmed to room temperature and stirred for 3 hours. The solution was cooled to 0- 5°C and sodium hydroxide solution added to a final pH of about 7. The aqueous layer was separated and extracted with DCM (13ml), then the combined organic layers were washed with water, dried over sodium sulphate, then concentrated under vacuum to give the title compound as a solid (33.3g).

1 H NMR (300 MHz, CHCI3-d): δ(ppm): 2.35 (m, 2H); 2.95 (m, 1 H); 3.12 (m, 1 H); 3.78 (s, 3H); 4.89 (dd, 1 H); 5.18 (s, 2H); 7.00 (d, 2H); 7.10 (m, 1 H) ; 7.16 (m, 1 H) ; 7.29 (m, 1 H) ; 7.5 (t, 1 H) ; 7.85 (d, 2H) . Description 14: Methyl (5ffl-5-f4-r(2-fluorobenzvnoxylphenyl}-L-prolinate (D14)

Procedure 1 : Methyl (2S)-5-{4-[(2-fluorobenzyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole-2- carboxylate (D13) (392g) was dissolved in EtOAc (316OmL) in a hydrogenation reactor. 5% platinum on carbon (Engelhard code 44379, moisture content ca. 50%, 15.8g) was added, the reactor filled with hydrogen gas to a pressure of 2atm and the reaction mixture was stirred for approximately 1.5 hours. The reactor was depressurised and the spent catalyst filtered through Celite, washing through with EtOAc (2 x 50OmL, then further 20OmL). Aqueous saturated NaHCO₃ solution (600 mL) was added to the filtrate, followed by aqueous 13% w/w Na₂CO₃ solution (up to pH = 9, 100OmL). The mixture was stirred for 10 minutes and phases were then allowed to separate .The aqueous phase was removed and then the organic layer was washed once with brine (60OmL). The resulting solution was concentrated to dryness and the residue was purified by flash chromatography eluting with cyclohexane / ethyl acetate (1 :1 ) to afford the title compound (133 g); ¹H NMR (600 MHz, DMSO-d6) δ(ppm): 7.55 (dt, 1 H); 7.41 (m, 1 H); 7.34 (m, 2H); 7.23 (m, 2H); 6.97 (m, 2H); 5.12 (s, 2H); 4.09 (dd, 1 H); 3.83 (dd, 1 H); 3.66 (s, 3H); 2.97 (bs, 1 H); 2.04 (m, 2H); 1.94 (m, 1 H); 1.52 (m, 1 H). D14 was also prepared as follows:

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. The mixture was filtered through Hyflo, washing with ethyl acetate (272ml), then the filtrate was washed with aq sodium carbonate solution and brine, dried over sodium sulphate, then concentrated under vacuum, and the residue dried to give the title compound as a crude oil (also containing some of the anti isomer),

1 H NMR (300 MHz, CHCI3-d): δ(ppm): 1.7 (m, 1 H); 2.18 (m, 4H) ; 3.75 (s, 3H); 3.91 (m, 1 H) ; 4.15 (m, 1 H) ; 5.13 (s, 2H); 6.96 (d, 2H) ; 7.07 (m, 1 H); 7.15 (m, 1 H); 7.30 (m, 1 H) ; 7.38 (d, 2H); 7.5 (t, 1 H).

Examples

Example 1 : (5/?)-5-(4-{r(2-Fluorophenyl)methylloxy)phenyl)-L-prolinamide (ED

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 0-10⁰C. 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 15-20⁰C 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 60⁰C. Toluene (130ml) and methanol (0.32ml) were added to the residue and the mixture heated to 70-75°C. The resulting solution was then cooled to 15-20⁰C and stirred for 1 hour. The solid was filtered, washed with toluene and dried at 45-50°C to give the title compound (21.8g) as a solid.

1H NMR (500 MHz, DMSO-d6) δ(ppm): 1.39 (m, 1 H) ; 1.84 (m, 1 H) ; 2.04 (m, 2H) ; 3.54 (m, 1 H) ; 4.09 (m, 1 H) ; 5.12 (s, 2H); 6.96 (d, 2H); 7.15 (m, 1 H); 7.25 (m, 2H) ; 7.34 (d, 2H) ; 7.41 (m, 2H) ; 7.55 (t, 1 H). E1 was also prepared as follows:

Procedure 2: Methyl (5R)-5-{4-[(2-fluorobenzyl)oxy]phenyl}-L-prolinate (D14) (127g) was dissolved in 7N NH₃ solution in MeOH (1016ml_) and the mixture was stirred at room temperature for 24hrs. Further 7N NH₃ solution in MeOH (63ml_) was added and the mixture stirred for a further 15 hours. The solvent was removed under reduced pressure and MeOH (635ml_) was added. The solution was evaporated to dryness and the white solid obtained was left under high vacuum over the weekend. The white solid was suspended in a mixture of MTBE/ Toluene 1 :1 (254ml_) at 2O⁰C and stirred for 1 hr. The suspension was filtered and the solid washed with MTBE (254ml_). The white solid was dried at 4O⁰C overnight under vacuum affording 122.4g of material. This material was resuspended in a mixture of MTBE/toluene 1 :1 (245ml_) and stirred at room temperature for 1 hour. The mixture was filtered and the solid was washed with MTBE (245ml_). The white solid obtained was dried at 4O⁰C overnight under vacuum to give the title compound (109g). ¹H NMR (600 MHz, DMSO-d6) δ(ppm): 7.54 (td, 1 H); 7.41 (m, 1 H); 7.38 (m, 2H); 7.34 (d, 2H); 7.24 (m, 2H); 7.13 (bs, 1 H); 6.96 (d, 2H); 5.12 (s, 2H); 4.09 (dd, 1 H); 3.55 (dd, 1 H); 3.24 (bs, 1 H); 2.07 (m, 1 H); 2.00 (m, 1 H); 1.85 (m, 1 H); 1.40 (m, 1 H).

Example 2j (5R)-5-(4-{[(2-fluorophenyl)methyl1oxy)phenyl)-L-prolinamide hydrochloride (E2):

.HCI

Procedure 1 : To a solution of 1 ,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate (D10, 51 mg, 0.123mmol) in a mixture of ethyl acetate (0.9ml) and methanol (1 ml) was added acetylchloride (28 μl, 2.5eq) at 0⁰C. The mixture was shaken for 1.5h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (42mg, quant.); Chiral HPLC: Column: chiralcel OD 10 urn, 250 x 4.6 mm; Mobile phase: A: n-Hexane; B: Ethanol; Gradient: isocratic 30% B; Flow rate: 0.8 ml/min; UV wavelength range: 200-400 nm; Analysis time: 22 min; ret. time: 12.0min. [α]_D = -30.5°. MS: (ES/+) m/z: 315 [MH⁺], C18H19FN2O2 requires 314; ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (br. s., 1 H), 8.13 (br. s., 1 H), 7.94 (s, 1 H), 7.60 - 7.77 (m, 1 H), 7.51 (dt, 1 H), 7.43 (d, 2H), 7.34 - 7.41 (m, 1 H), 7.23 (d, 1 H), 7.18 (dd, 1 H), 7.05 (d, 2H), 5.13 (s, 2H), 4.49 -

4.60 (m, 1 H), 4.19 - 4.28 (m, 1 H), 2.17 - 2.38 (m, 2H), 2.05 - 2.16 (m, 1 H), 1.92 - 2.03 (m, 1 H).

Example 2 was also prepared as follows:

Procedure 2: ((5/?)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1 , 109g) was dissolved in DCM (654ml_) and Et₂O (654ml_) was added at room temperature. HCI 1 N in Et₂O (380.4ml_) was added dropwise at room temperature. The suspension was cooled to O⁰C and stirred at this temperature for 1 hr. The solid was filtered, washed with Et₂O (2 x 327ml_) and dried at 4O⁰C under vacuum overnight to afford Form 1 crystals of the title compound (121.24g). ¹H NMR (600 MHz, DMSO-d6) δ(ppm): 10.72 (bs, 1 H); 8.10 (bs, 1 H); 8.08 (s, 1 H); 7.72 (s, 1 H); 7.56 (td, 1 H); 7.49 (d, 2H); 7.43 (qd, 1 H); 7.25 (m, 2H); 7.10 (d, 2H); 5.17 (s, 2H);

4.61 (dd, 1 H); 4.30 (dd, 1 H); 2.32 (m, 2H); 2.16 (m, 1 H); 2.02 (m, 1 H).

Procedure 3: ((5/?)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1 , 10g, 31.8mmol) was dissolved in DCM (50ml) and stirred with charcoal (1g), then filtered, washing with DCM (30ml). The residue was concentrated under vacuum, removing about 20ml of DCM. Ether (60ml) was added, followed by a solution of HCI in ether (0.84N, 40ml), and the mixture was then stirred at 20-25⁰C for 30 min, then cooled to 0-5⁰C and stirred for 2 hours. The solid was filtered, washed with ether, then dried at room temperature to give Form 1 crystals of title compound (10.25g). ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 2.04 (m, 1 H); 2.18 (m, 1 H); 2.32 (m, 2H); 4.34 (m, 1 H); 4.64 (m, 1 H); 5.18 (s, 2H) ; 7.10 (d, 2H) ; 7.25 (m, 2H); 7.40-7.60 (m, 4H); 7.77 (s, 1 H) ; 8.24 (s, 1 H) ; 11.03 (b, 1 H).

Procedure 4: In a round bottom flask, a solution of ((5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1 , 1.4g, 4.45mmol) in ethylacetate

(14ml) and MeOH (2.5ml) at 0°C was treated with HCI 1 M in diethylether (1.1eq,

4.89ml).The precipitation occurred quite soon and the mixture was stirred at 0⁰C for

1 h. The mixture was then diluted with dry diethylether (10ml) and then filtered on a

Gooch filter (porosity 4, diameter 5cm). The cake was washed on the filter with dry diethylether (2x20ml) and the white solid thus obtained was transferred into a round bottom flask, dried under high vacuum at 40⁰C for 2h and then at room temperature for 18hours. A white solid was obtained (1.51g) of Form 1 crystals of the title compound.

Procedure 5: ((5/?)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1 , 25g, 79.5mmol) was dissolved in ethyl acetate (750ml) and stirred with charcoal (2.5g), then filtered, washing with ethyl acetate (125ml). To the filtrate and washings, a solution of HCI in ether (1 N, 103ml), was added over 30 minutes at 20-25⁰C and the mixture was then stirred at 20-25°C for 30 min, then cooled to 0-5⁰C and stirred for 2 hours. The solid was filtered, washed with ethyl acetate (2 x 70ml), then dried at room temperature to give Form 1 crystals of the title compound. (25.5g).

Unique and discriminating peaks of Form 1 of the title compound of Example 2 have been identified and are illustrated in the table below:

Melting point: 230 ° C.

Example 4j (5R)-5-(4-{r(2-fluorophenyl)methylloxy}phenyl)-L-prolinamide methanesulfonate (E4):

EtOAc (6ml) was added to (5R)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L- prolinamide (E1 , 300 mg) and this was heated at 60⁰C for an hour to dissolve the compound. Then methanesulfonic acid (65μl, 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 (0-40⁰C) for 2 days. The compound was isolated by filtration as a white solid, washed with EtOAc and dried in vacuo at 40⁰C overweek-end to afford 335 mg of the title compound.

Melting point: 192° C.

Claims

1. 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 compound (5/?)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L- prolinamide or a pharmaceutically acceptable salt or solvate thereof.

2. Method according to claim 1 wherein the compound is (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride.

3. Method according to claim 1 wherein the subject is a human.

4. Compound (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 for use in combination therapy in the treatment of epilepsy and related disorders.

5. (5/?)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride and one or more anticonvulsant and / or anti-epileptic agents for use in combination therapy in the treatment of epilepsy and related disorders.

6. Use of compound (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 for the treatment of epilepsy and related disorders in combination therapy.

7. Use according to claim 6 where the compound is (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride.