WO2007052134A1

WO2007052134A1 - (2s)-2-aminomethyl-5-ethyl heptanoic acid its pharmaceutical use

Info

Publication number: WO2007052134A1
Application number: PCT/IB2006/003087
Authority: WO
Inventors: David James Rawson; Jacob Bradley Schwarz
Original assignee: Pfizer Limited
Priority date: 2005-11-04
Filing date: 2006-10-23
Publication date: 2007-05-10

Abstract

The present invention relates to (2S)-2-aminomethyl-5-ethyl-heptanoic acid and the pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing, and the uses of (2S)-2-aminomethyl-5-ethyl-heptanoic acid.

Description

(2S)-2-AMINOMETHYL-5-ETHYL HEPTANOIC ACID ITS PHARMACEUTICAL USE

This invention relates to (2S)~2-aminomethyl-5-ethyl-heptanoic acid and the pharmaceutically acceptable salts and solvates thereof and to processes for the preparation of, intermediates used in the 5 preparation of, compositions containing, and the uses of such compounds.

(2S)-2-aminomethyl-5-ethyl-heptanoic acid is an alpha-2-delta (α2δ) receptor ϋgand (also known as an alpha-2-delta ligand) and as such is useful in the treatment of a number of different diseases. An alpha-2-delta receptor ligand is a molecule which binds to any sub-type of the human calcium channel

10 alpha-2-delta subunit. The calcium channel alpha-2-delta subunit comprises a number of sub-types which have been described in the literature (e.g. type 1 , J. Biol. Chem., 1996, 271 (10), 5768-76; types 2 and 3, J. Membr. Biol., 2001 , 184(1 ), 35-43 and MoI. Pharmacol., 2001 , 59(5), 1243-1248; and type 4, MoI. Pharmacol., 2002, 62(3), 485-496). Alpha-2-delta receptor ligands are also sometimes known as GABA analogues.

15

International Patent Application WO-A-2003/082807 discloses the racemate 2-aminomethyl-5-ethyl- heptanoic acid and its use in the treatment of pain. Apart from relevant pharmacological activity, a drug must also have suitable absorption, distribution, metabolism and excretion (ADME) characteristics in order to demonstrate useful therapeutic activity. In particular, it must possess a suitable half-life.

20 The racemate, 2-aminomethyl-5-ethyl-heptanoic acid, does not have a sufficiently long predicted half- life to be ideal for once-a-day dosing in humans. A half-life long enough to allow once-a-day dosing is often desirable as it increases patient compliance.

It has now unexpectedly been found that there is a three-fold increase in predicted human half-life for 25 (2S)-2-aminomethyl-5-ethyl-heptanoic acid when compared with the racemate disclosed in WO-A- 2003/082807. (2S)-2-Aminomethyl-5-ethyl-heptanoic acid is thus highly suitable for once-a-day dosing in humans. This is a significant improvement over the racemate, 2-aminomethyl-5-ethyl-heptanoic acid, and over the currently marketed alpha-2-delta ligands (gabapentin and pregabaliri) which are administered two or three times a day. ^'30

The invention therefore provides (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid Pharmaceutically acceptable salts of (2S)-2-aminomethyl-5-ethyl-heptanoic acid include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of (2S)-2-aminomethyl-5-ethyl-heptanoic acid may be prepared by one or more of three methods:

(i) by reacting (2S)-2-aminomethyl-5-ethyl-heptanoic acid with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of (2S)-2- aminomethyl-5-ethyl-heptanoic acid or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of (2S)-2-aminomethyl-5-ethyl-heptanoic acid to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. (2S)-2-Aminomethyl-5-ethyl-heptanoic acid may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition')- The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

(2S)-2-Arninomethyl-5-ethy!-heptanoic acid may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising (2S)-2-aminomethyl-5-ethyl- heptanoic acid or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non- stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'therm otropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COCTNa⁺, -COOX⁺, or -SO₃-Na⁺) or non-ionic (such as -N^'N⁺(CH₃)₃) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshome and A. Stuart, 4^th Edition (Edward Arnold, 1970).

Hereinafter all references to (2S)-2-aminomethyl-5-ethyl-heptanoic acid are taken to embrace salts, solvates, multi-component complexes and liquid crystals thereof. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. Also included in the present invention are all tautomeric forms of (2S)-2-aminomethyl-5-ethyl-heptanoic acid. For example, at neutral pH the compound will exist as a zwitterions with CO₂ ^" and NH₃ ⁺ groups. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or /-lysine, or racemic, for example, cf/-tartrate or d/-arginine.

The invention includes all polymorphs and crystal habits of (2S)-2-aminomethyl-5-ethyl-heptanoic acid, prodrugs as hereinafter defined and isotopically-labeled (2S)-2-aminomethyl-5-ethyl-heptanoic acid.

As indicated, so-called 'prodrugs' of (2S)-2-aminomethyl-5-ethyl-heptanoic acid are also within the scope of the invention. Thus certain derivatives of (2S)-2-aminomethyl-5-ethyl-heptanoic acid which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into (2S)-2-aminomethyl-5-ethyl-heptanoic acid, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in (2S)-2-aminomethyl-5-ethyl-heptanoic acid with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs of (2S)-2-aminomethyl-5-ethyl-heptanoic acid in accordance with the invention include

(i) an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality is replaced by (Ci-C₈)alkyl;

(ii) an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality is/are replaced by (Ci-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

The present invention includes all pharmaceutically acceptable isotopically-labelled analogues of (2S)- 2-aminomethyl-5-ethyl-heptanoic acid wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in (2S)-2-aminomethyl-5-ethyl-heptanoic acid include is soottooppeess ooff hhyyddrrooggeenn,, ssuucchh aass ²²HH aanndd ³³HH,, cc;arbon, such as ¹¹C, ¹³C and ¹⁴C, , nitrogen, such as ¹³N and ⁵N, and oxygen, such as ¹⁵0, ¹⁷O and ¹⁸O.

Certain isotopically-labelled analogues of (2S)-2-aminomethyl-5-ethyl-heptanoic acid, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled (2S)-2-aminomethyl-5-ethyl-heptanoic acid can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Also included within the scope of the invention are metabolites of (2S)-2-aminomethyl-5-ethyl- heptanoic acid, that is, compounds formed in vivo upon administration of the drug.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

(2S)-2-aminomethyl-5-ethyl-heptanoic acid, being an alpha-2-delta receptor ligand, is potentially useful in the treatment of a wide range of disorders. The treatment of pain, particularly neuropathic pain, is a preferred use.

Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (nonmyelinated). The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.

Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury. This injury often leads to abnormalities in sensory nerve fibres associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288,

1765-1768).

Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms.

Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli

(allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating. Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.

Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (Gl) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.

Other types of pain include:

• pain resulting from musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis; • heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;

• head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and • orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.

Apart from pain, (2S)-2-aminomethyl-5-ethyl-heptanoic acid is potentially useful in the treatment of any disease or condition which is treatable using an alpha-2-delta receptor ligand. Such conditions include epilepsy, gastrointestinal disorders, premature ejaculation, burning mouth syndrome, bladder disorders (such as over active bladder), faintness attacks, fibromyalgia, hypokinesia, cranial disorders, hot flashes, essential tremor, chemical dependencies and addictions, withdrawal symptoms associated with dependencies or addictions, addictive behaviours, spasticity, arthritis, inflammatory disorders (e.g. rheumatoid arthritis, osteoarthritis, psoriasis) diuresis, premenstrual syndrome, premenstrual dysphoric disorder, tinnitus, gastric damage, Down's syndrome, demyelinating diseases (e.g. multiple sclerosis and amylolateral sclerosis, cerebral vascular disorders due to acute or chronic cerebrovascular damage (e.g. cerebral infarction, subarachnoid haemorrhage or cerebral oedema), head trauma, spinal cord trauma and neuronal damage that occurs, for instance, during stroke, in cardiac bypass surgery, in incidents of intracranial haemorrhage, in perinatal asphyxia, in cardiac arrest and in status epilepticus. Alpha-2-delta receptor ligands may also be useful in the treatment of delirium, dementia and amnestic and other cognitive or neurodegenerative disorders (e.g. Parkinson's disease, Huntingtons's disease, Alzheimer's disease, senile dementia, memory disorder, vascular dementia). They may also be useful in the treatment of movement disorders such as akinesias, dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, palsys, akinetic-rigid syndrome and extra-pyramidal movement disorders. They may also be useful in the treatment of sleep disorders, mood disorders, depression, depressive disorders, bipolar disorders, anxiety disorders, panic, borderline personality disorder, schizophrenia, psychotic disorders, behavioural disturbances associated with mental retardation, autistic disorder and conduct disorder.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section and the Preparations section, or by similar methods thereto. The present invention also encompasses any one or more of these processes for preparing (2S)-2-aminomethyl-5- ethyl-heptanoic acid, in addition to any novel intermediates used therein.

Diverse methods exist for the preparation of chiral and racemic beta-amino acids. Such methods can be found in "Enantioselective Synthesis of β-Amino Acids", Juaristi, Eusebio; Editor. USA, 1997, Wiley- VCH, New York, N.Y.

The methods described below are illustrative of methods that can be used for the preparation of the compound but are not limiting.

According to a first process, (2S)-2-aminomethyl-5-ethyl-heptanoic acid (the compound of formula (I)) may be prepared from a compound of formula (IV) as shown in scheme 1 , below:

(b)

Scheme 1

The compound of formula (II) may be obtained as described in Organic Letters, 2000; 2(22); 3527- 3529. Step (a): The compound of formula (II) is de-protonated using a suitable base, and the resulting anion quenched by addition of the alkyating agent, typically the bromide (Vl), to provide the compound of formula (III). The reaction is typically achieved by the treatment of (II) with a strong base, for example, lithium diisopropylamide (LDA), lithium hexamethyldisilylazide (LHMDS), or sodium hexamethyldisilylazide (NaHMDS), optionally in the presence of an additive, (e.g. lithium chloride (LiCI)) in a suitable solvent (e.g. tetrahydrofuran (THF), ether) at low temperature, for example at a temperature of from -15⁰C to O⁰C for about 1 hour, followed by the quenching of the resulting anion with the alkenyl bromide (Vl). In a preferred procedure, a solution of 1 equivalent of the compound of formula (II) in THF is treated with 3.2 equivalents LHMDS and 4 equivalents LiCl, at a temperature of from -15⁰C to -5⁰C for about 1 hour followed by treatment with 1 equivalent of the alkenyl bromide (Vl), keeping the temperature below -5⁰C and the reaction is allowed to warm to room temperature.

The alkenyl bromide (Vl) may be prepared from commercially available starting materials using standard chemical transformations as exemplified in Preparations 1 and 2.

Step (b): The compound of formula (III) may be reduced to provide the compound of formula (IV). This may be achieved with hydrogen and a suitable catalyst, (for example 5-10% palladium on charcoal or platinum oxide), In a preferred procedure, a solution of the amide of formula (III) in ethyl acetate is reduced using 4 atmospheres of H₂, in the presence of 10% palladium on charcoal, at room temperature for 72 hours.

Alternatively compound (IV) may be prepared in one step by replacing the alkenyl bromide (Vl) with an alkyl halide (Via) in step (a) as in scheme 1. The alkly bromide may be prepared according to the processes described by Bestmann et al. (Liebigs Ann. Chem. 1979, 1189-1204) and Pinazzi et al. {Bull. Soc. Chim., 1975, 1-2, 201-205). The alkyl iodide may be prepared by analogous processes.

Step (c): The compound of formula (IV) may be hydrolysed to provide the compound of formula (I). This reaction may be achieved under neutral, basic or acidic catalysis, but typically under neutral conditions. The reaction is performed in water, optionally in the presence of a co-solvent (e.g. dioxan, THF) at reflux for about 4 days. In a preferred procedure, a solution of the amide of formula (IV) in wateπdioxan (1 :1 by volume) is heated at reflux for from 110 to 120 hours.

Alternatively, the compound of formula (I), may be prepared by changing the order of steps (b) and (c) as shown in Scheme 2.

H

Scheme 2 (I)

According to a second process, (2S)-2-aminomethyl-5-ethyl-heptanoic acid (compound (I)), may be prepared from a compound of formula (IX) as shown in scheme 3.

(IX) Scheme 3

Compounds of formula (VII) may be obtained according to the methods of Juaristi et al. Tetrahedron Asymmetry, 1996, 2233-46.

Step (f): The compound of formula (VII) is treated with a suitable base, and the resulting anion is quenched by addition of an alkylating agent of formula (Via) to provide the compound of formula (VIII). The reactipn may be achieved by treatment of the compound of formula (VII) with a strong base, for example, LDA, LHMDS or NaHMDS, in a suitable solvent (e.g. THF, ether) at a temperature of from - 78⁰C to -6O⁰C, for example -78°C, for about 1 hour, followed by quenching of the resulting anion with the alkyl bromide, at a temperature of from -78⁰C to about room temperature.

Step (g): The compound of formula (IX) may be prepared by treatment of the compound of formula (VIII) with a suitable base, and quenching of the resulting anion with aqueous acid. The reaction may be achieved by treatment of. the compound of formula (VIII) with a strong base, for example, LDA, LHMDS or NaHMDS, in a suitable solvent (e.g. THF, ether) at very low temperature, for example at a temperature of from about -78° to about -6O⁰C for about 3 hours, followed by quenching of the resulting anion with aqueous acid.

Step (h): Hydrolysis of the. compound of formula (IX) provides the compound of formula (I). This reaction may be achieved under basic or acidic catalysis, but is typically carried out under aqueous acidic conditions (e.g. hydrochloric acid (HCl) or sulphuric acid (H₂SO₄)), optionally in the presence of a suitable solvent (e.g. THF) at reflux for about 24 hours. According to a third process, the compound of formula (I) may be prepared from a compound of formula (XIII) according to scheme 4.

Scheme 4

Steps (f) and (h) are as described above for scheme 3.

According to a fourth process, the compound of formula (I) may be prepared from a compound of formula (XVII) by the method outlined in scheme 5.

(XVII) (I)

Scheme 5

R is a suitable protecting group such as (Ci-C₆)alkyl.

Step (i): The aldehyde (XIV) may undergo Knoevenagel condensation with a cyanoacetate derivative to give the compound of formula (XV) in an analogous manner to that described in Journal of Organic Chemistry, 1961 , 26, 2738-2740. The aldehyde (XIV) is described in Tetrahedron 1988, 44(4)1091 - 1106.

Step (j): Reduction of a compound of formula (XV) to a compound of formula (XVI) may be carried out by hydrogenation in a suitable solvent, typically ethanol, in the presence of a metal catalyst (e.g. platinum oxide, palladium on charcoal). Step (k): Resolution of a compound of formula (XVI) may be achieved by formation of a chiral salt (e.g. the (+) di-o-tolyl tartrate or (L)-dibenzoyl tartrate salt)and recrystallisation, followed by reformation of the free amine.

Step (m): The compound of formula (I) may be prepared by hydrolysis of a compound of formula (XVII) under acidic or basic conditions, typically using HCI, in dioxan, at a temperature of 8O⁰C, for about 18 hours.

Compound (I) may alternatively be prepared by stereospecific hydrolysis of compound (XVI) with an enzyme (e.g. pig liver esterase, lipase).

A compound of formula (XVI) may alternatively be prepared from a compound of formula (XVIII) according to scheme 6.

Scheme 6

Step (n): The alkenyl bromide (Vl), as exemplified in Preparations 1 and 2, may be used to alkylate a cyanoacetate derivative in the presence of a base (e.g. potassium carbonate) and a solvent (e.g. acetonitrile) to give a compound of formula (XVIII).

Step (o): Reduction of a compound of formula (XVIII) to a compound of formula (XVI) may be carried out by hydrogenation in a suitable solvent, typically ethanol, in the presence of a metal catalyst (e.g. platinum oxide or palladium on charcoal).

The compound of formula (I) may also prepared by analogy with the methods described in WO-A- 2003/082807 and references therein, and also by the method of Lavielle et al in European Journal of Organic Chemistry, 2000(1 ), 83-89.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may be administered as a crystalline or amorphous product. Such products may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. (2S)-2-Aminomethyl-5-ethyl-heptanoic acid may be administered alone or in combination with one or more other drugs (or as any combination thereof). Generally, (2S)-2-aminomethyl-5-ethyl-heptanoic acid will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of (2S)-2-aminomethyl-5-ethyl-heptanoic acid and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, IJ. (6), 981-986, by Liang and Chen (2001 ).

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste- masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically pliable water-soluble or water- swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise (2S)-2-aminomethyl-5-ethyl-heptanoic acid, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, (2S)-2-aminomethyl-5-ethyl- heptanoic acid may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocollόids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.

Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. (2S)-2-Aminomethyl-5-ethyl-heptanoic acid may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of (2S)-2-aminomethyl-5-ethyl-heptanoic acid when used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus (2S)-2-aminomethyl-5-ethyl-heptanoic acid may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(d/-lactic-coglycolic)acid (PGLA) microspheres.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may also be administered topically, (intra)dermally, or transdermal^ to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of (2S)-2-aminomethyl-5-ethyl-heptanoic acid comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of (2S)-2-aminomethyI-5- ethyl-heptanoic acid, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of (2S)-2-aminomethyl-5-ethyl-heptanoic acid per actuation and the actuation volume may vary from 1μl to 100μl. A typical formulation may comprise (2S)-2-aminomethyl- 5-ethyl-heptanoic acid, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff". The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

(2S)-2-Aminomethyl-5-ethyl-heptanoic acid may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

For administration to human patients, the total daily dose of (2S)-2-aminomethyl-5-ethyl-heptanoic acid is typically in the range 1 mg to 1000 mg depending, of course, on the mode of administration. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

An alpha-2-delta receptor ligand may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain. For example, an alpha-2-delta receptor ligand, particularly (2S)-2-aminomethyl-5-ethyl- heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:

• an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

• a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

• a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;

• a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

• an H₁ antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

• a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;

• an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-

3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4- dihydro-2(1 H)-quinolinone; ^• • an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1 ,2,3,4-tetrahydroisoquinol-2- yl)-5-(2-pyridyl) quinazoline;

• a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

• an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate or valproate; • a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (αR,9R)-7-

[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H- [1 ,4]diazocino[2,1 -g][1 ,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1 R)-1 -[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1 ,2-dihydro-3H- 1 ,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

• a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

• a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; • a coal-tar analgesic, in particular paracetamol; • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

• a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist (e.g. capsazepine);

• a beta-adrenergic such as propranolol;

• a local anaesthetic such as mexiletine;

• a corticosteroid such as dexamethasone; • a 5-HT receptor agonist or antagonist, particularly a 5-HT_1B/ID agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

• a 5-HT_2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

• a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)- 3-buten-1 -amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

• Tramadol®;

• a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3- n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a- hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1 ,4- dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl- 7-propyl-3H-imidazo[5,1-f][1 ,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3- ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2- propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7/-/-pyrazolo[4,3- cOpyrimidin-7-one, 5-[2-ethoxy-5-(4-ethyIpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2- methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4- methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2- ylmethyl)pyrimidine-5-carboxamide, 3-(1 -methyl-7-oxo-3-propyl-6,7-dihydro-1 H-pyrazolo[4,3- d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; • a cannabinoid;

• metabotropic glutamate subtype 1 receptor (mGluRI) antagonist;

• a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

• a noradrenaline (norepinephrine) reuptake inhibitor, suGh as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S.S)-reboxetine; • a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;

• an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L- homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1- iminoethyl)amino]ethyl]-2-methyi-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1- iminoethyl)amino]-5-heptenoic acid, 2-[[(1 R,3S)-3-amino-4- hydroxy-1-(5-thiazolyl)-butyl]thio]- 5-chloro-3-pyridinecarbonitrile; 2-[[(1 R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4- chiorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyI)phenyl]thio]-5- thiazolebutanol,

2-[[(1 R,3S)-3-amino-4-hydroxy-1 -(5-thiazolyl) butyl]thio]-6-(trifiuoromethyl)-3 pyridinecarbonitrile, 2-[[(1 R,3S)-3- amino-4-hydroxy- 1 -(5-thiazoIyl)butyi]thio]-5- chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyldisulfide; • an acetylcholinesterase inhibitor such as donepezil;

• a prostaglandin E₂ subtype 4 (EP4) antagonist such as Λ/-[({2-[4-(2-ethyl-4,6-dimethyl-1 H- imidazoμ.δ-clpyridin-i-yOphenyOethylJaminoJ-carbonyO^-methylbenzenesulfonamide or 4- [(1 S)- 1 -({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

• a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)- cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870,

• a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H- pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3- pyridylmethyl),1 ,4-benzoquinone (CV-6504); • a sodium channel blocker, such as lidocaine;

• a 5-HT3 antagonist, such as ondansetron;

and the pharmaceutically acceptable salts and solvates thereof.

Where a combination of active compounds is to be administered, two or more pharmaceutical compositions may conveniently be combined in the form of a kit suitable for co-administration of the compositions. Such a kit comprises two or more separate pharmaceutical compositions, at least one of which contains an alpha-2-delta receptor ligand, particularly (2S)-2-aminomethyl-5-ethyl-heptanoic acid, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

Such a kit is particularly suitable for administering different dosage forms, for example oral and parenteral formulations, for administering separate compositions at different dosage intervals, or for titrating separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

It will be appreciated that what the invention provides, and what will be claimed, is as follows; (i) the compound (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof;

(ii) (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament;

(iii) (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disease for which an alpha-2-delta receptor ligand is indicated.

(iv) (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of pain.

(v) the use of (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a disease for which an alpha- 2-delta receptor ligand is indicated;

(iv) the use of (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of pain;

(vii) a method of treating a disease or condition for which an alpha-2-delta receptor ligand is indicated in a mammal, including a human being, comprising administering an effective amount of (2S)- 2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof;

(viii) a method of treating pain in a mammal, including a human being, comprising administering an effective amount of (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof;

(ix) a pharmaceutical composition including (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient;

(x) a process for the preparation of (2S)-2-aminomethyl-5-ethyl-heptanoic acid or a pharmaceutically acceptable salt or solvate thereof;

(ix) certain novel intermediates disclosed herewithin; and (xii) a combination of (2S)-2-aminomethyl-5-ethyl-heptanoic acid or a pharmaceutically acceptable salt or solvate thereof and one or more further pharmacologically active compounds.

The following Examples illustrate the preparation of the compound of formula (I).

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The mass spectra (MS) were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). The following abbreviations have been used for common solvents: CDCI₃, deuterochloroform; THF, tetrahydrofuran. Example 1 (2SV2-(AminomethvD-5-ethvlheptanoic acid

Method A

5% Palladium on carbon (109g) was added to a solution of the alkene of Preparation 4 (1.2kg, 6.5mol) in 10% acetic acid in water (12.1 L) and the mixture was stirred under an atmosphere of hydrogen at 60psig and 25°C for 5 hours. The reaction mixture was filtered through Arbocel^® and the filter cake was washed with two portions of 20% acetic acid in water (2 x 12.1 L). The filtrate was concentrated to dryness in vacuo. The residue was slurried in water (24.2L) and concentrated to dryness in vacuo. The residue was slurried in acetonitrile (24.2L) and concentrated to dryness in vacuo before being diluted with acetonitrile (24.2L) and filtered. The filter cake was washed with acetonitrile (24.2L) and dried in a vacuum oven at 5O⁰C for 18 hours to yield the title compound as a white solid (1.18kg, 6.3mol, 97%) ¹H-NMR (CD₃OD; 400MHz): δ θ.86 (t, 6H), 1.15-1.23 (m, 1 H), 1.29-1.36 (m, 6H), 1.44-1.53 (m, 1 H), 1.64-1.73 (m, 1 H), 2.33-2.40 (m, 1 H), 2.93-3.03 (m, 2H). LRMS m/z APCI 188 [MH]⁺

Method B

The amide of Preparation 5 (8.6g, 0.026mol) was dissolved in 1 ,4-dioxane (100ml), water (100ml) was added and the reaction mixture heated at reflux for 116 hours. The mixture was filtered through Arbocel^® and the filtrate evaporated in vacuo. The crude material was triturated with acetonitrile then recrystalised from water to yield the title compound as a white solid (2.9g, 0.0156mol, 60%).

The following Preparations illustrate the preparation of certain intermediates used to prepare the above Examples. Preparation 1

3-Ethylpent-1-en-3-ol

To a 1 M solution of vinyl magnesium bromide in tetrahydrofuran (400ml, 0.4mol) stirring at O⁰C, was added dropwise a solution of 3-pentanone (34.7ml, 0.33mol) in tetrahydrofuran (30ml), maintaining the temperature between 5-15⁰C. The reaction mixture was allowed to warm to room temperature overnight then quenched with a saturated aqueous solution of ammonium chloride (20ml). The mixture was diluted with diethyl ether (400ml), washed with water (2x100ml), dried over magnesium sulphate, filtered and evaporated in vacuo. The title compound was obtained as a yellow oil (30.7g, 0.269mol,

82%).

¹H-NMR (CDCI₃, 400MHz): δ 0.85 (t, 6H), 1.5-1.6 (m, 4H), 5.10-5.25 (m, 2H), 5.75-5.85 (m, 1 H).

Preparation 2

1 -Bromo-3-ethylpent-2-ene

48% aqueous Hydrobromic acid (74.58g, 0.44mol) was added to a solution of the alkene of Preparation 1 (55.8g, 49mmol) in pentane (950ml) and the reaction mixture stirred at room temperature for 5 hours then left to stand for 18 hours. The layers were separated and the organic layer washed with water (2x200ml), dried over magnesium sulphate, filtered and evaporated in vacuo. The crude material was returned to the reaction conditions for a further 2 hours, left to stir at room temperature overnight, then worked up as previously described. The crude material was purified by fractional distillation. The title compound was obtained as a colourless oil with a boiling point of 47-5O⁰C at 10 millibar (47.2g, 0.27mol, 55%).

¹H-NMR (CDCI₃, 400MHz): δ 1.0 (m, 6H), 2.1-2.2 (m, 4H), 4.05 (d, 2H), 5.5 (t, 1 H).

Preparation 3 (2S)-2-(Aminomethyl)-5-ethyl-N-r(1 S,2S)-2-hvdroxy-1-methyl-2-phenylethyll-N-methylhept-4-enamide

To a suspension of ₀3-amino-N-((1 S,2S)-2-hydroxy-1-methyl-2-phenylethyl)-Λ/-methylpropanamide hydrochloride {Org. Lett, 2, 22, 2000, 3527-3530) (18kg, 66.0mol) in tetrahydrofuran (157L) was added 40% NaOH in water (4.6L, 66.0mol) over 1 hour at 2O⁰C. The reaction mixture was then filtered, diluted with tetrahydrofuran (75L) and concentrated by atmospheric pressure distillation until 75L of distillate had been collected. The slurry was then diluted with tetrahydrofuran (75L) and concentrated by atmospheric pressure distillation until 75L of distillate had been collected.

The solution of 3-amino-Λ/-((1 S,2S)-2-hydroxy-1-methyl-2-phenylethyl)-Λ/-methylpropanamide free base was then added to a powdered, dried lithium chloride (16.8kg, 396mol) and stirred vigorously for 1 hour whilst being cooled to -1O⁰C under nitrogen. To the reaction mixture was added a solution of 1 ,1 ,1 ,3,3,3-hexamethyldisilazane lithium salt in tetrahydrofuran (238L, 0.944moldm^'3, 224mol) over 3.5 hours, maintaining reaction solution temperature below -5°C. The solution was then cooled to -15°C and stirred at that temperature for 1 hour. A solution of the ally! bromide of Preparation 2 (12.9kg, 72.6mol) in tetrahydrofuran (7.8L) was added over 1 hour, maintaining the reaction temperature below -5⁰C. The reaction mixture was allowed to warm to 2O⁰C over 7 hours then quenched with water (20L). To the reaction mixture was added 1 M HCI(aq) (269.2L, 269.2mol) and the biphasic mixture was stirred for 15 minutes before allowed to separate.

The aqueous layer was removed and 2M NaOH(aq) (134.6L, 269.2mol) was added and the biphasic mixture stirred for 15 minutes. The biphasic mixture was allowed to separate and the aqueous layer was removed. The reaction mixture was then concentrated by atmospheric pressure distillation until 370L of distillate was collected. The solution of the title compound (assumed to be 21.9kg, 68.9mol) in tetrahydrofuran (~80L) was used directly in Preparation 4.

¹H-NMR (CDCI₃, 400MHz): δ 0.92-1.00 (m, 9H), 1.96-2.06 (m, 4H), 2.08-2.17 (m, 1 H), 2.20-2.27 (m, 1 H), 2.80-2.88 (m, 2H), 2.91-2.93 (m, 1 H), 2.95 (m, 3H), 4.52 (d, 1 H), 4.81-4.85 (m, 1 H), 5.00 (t, 1 H), 7.24-7.39 (m, 5H). LRMS m/z APCI 333 [MH]⁺

Preparation 4 (2S)-2-(Aminomethyl)-5-ethylhept-4-enoic acid

To the amide of Preparation 3 (assumed to be 21.9kg, 68.9mol) in tetrahydrofuran (~80L) was added water (66L). The reaction mixture was then heated to 13O⁰C under an atmosphere of nitrogen at 130psig for 48 hours. The reaction mixture was cooled to 20⁰C. The biphasic solution was then diluted with water (65L) concentrated by atmospheric pressure distillation until 155L of distillate had been collected. To the slurry was added acetonitrile (130L) and the mixture was concentrated at atmospheric pressure until 130L of distillate had been collected. This dilution/concentration process was repeated a further 4 times before the precipitate was collected by filtration. The filter cake was washed with acetonitrile (132L) and the damp solid was dried at 50⁰C under vacuum for 48 hours to yield a pale coloured solid (9.25kg, 40% over two steps). The solid (5.3kg, 28.6mol) was recrystallised from acetonitrile (21.2L) and water (5.3L). The precipitate was collected by filtration at 10°C and found to be racemic (2S)-2-(aminomethyl)-5-ethylhept-4-enoic acid (2.04kg, 11 mol, 39%). The filtrate was concentrated in vacuo and diluted with 2-butanone (14.8L) and the slurry was stirred at 20°C for 30 minutes. The solid was filtered and the filter cake was washed with butanone (7.4L). The damp cake was dried in a vacuum oven at 50⁰C for 18 hours to yield title compound as white solid (1.2kg, 6.5mol, 23%, >99%ee). ¹H-NMR (CDCI₃, 400MHz): δ 1.00 (m, 6H), 2.00-2.15 (m, 4H), 2.20-2.35 (m, 1 H), 2.40-2.55 (m, 2H), 2.90-3.00 (m, 2H), 5.15 (t, 1 H). LRMS m/z APCI 186 [MH]⁺

Preparation 5 (2S)-2-(Aminomethvn-5-ethvl-N-f(1S.2S)-2-hvdroxv-1-methvl-2-Dhenvlethvn-N-methvlheptanamide

10% Palladium on carbon (1.2g) was added to a solution of the alkene of Preparation 3 (12.5g, 0.038mol) in ethyl acetate (250ml) and the reaction mixture stirred at room temperature, under 4.08 atmosheres of hydrogen for 72 hours. The reaction mixture was filtered through Arbocel^® and the solvent evaporated in vacuo. The crude material was recrystalised from diethyl ether to yield the title compound as a white solid (11.Og, 0.033mol, 87%).

¹H-NMR (CDCI₃, 400MHz): δ 0.81 (t, 6H), 0.96 (d, 3H), 1.10-1.35 (m, 9H), 1.52-1.60 (m, 1 H), 2.87-2.95 (m, 2H), 2.97 (s, 3H), 4.50 (d, 1 H), 4.87-4.91 (m, 1 H), 7.24-7.39 (m, 5H). LRMS m/z APCI 335 [MH]⁺

Pharmacokinetic Data

The pharmacokinetic characteristics of a compound can be assessed by administering it to a rat, taking blood samples at varying times points and analyzing the associated plasma for the concentration of compound present. If this is performed using an intravenous (iv) route of administration clearance data (CL) can be obtained, which is a measure of how rapidly the compound is eliminated from the systemic circulation. A volume of distribution (Vd) can also be determined, which is a measure of how extensively the compound is distributed throughout the body. A combination of the clearance and volume parameters can be used to predict the elimination half-life of the compound, which in turn will determine the dosing frequency required to achieve efficacious concentrations of the compound in man. Administration via the oral (po) route allows an assessment of the absorption of the compound, determination of the oral half-life and by comparing the systemic exposures following iv and po administration, a determination of the oral bioavailability.

The racemate 2-aminomethyl-5-ethyl-heptanoic acid was dosed orally, whilst the compound of the invention, (2S)-2-aminomethyl-5-ethyl-heptanoic acid, and the corresponding R enantiomer were dosed both orally and by intravenous (iv) administration to male CD rats. A dose of 1 mg/kg was used for both routes of administration. All compounds were formulated in ultra purfied water at a concentration of 1mg/ml, and a dose volume of 1.0ml/kg was used. Aliquots of blood (175μl) were collected - at the following time intervals post dose:

Pre-dose, 0.1 ^a, 0.25, 0.5, 0.75^b, 1 , 2, 4, 7, 10 and 24 hours.

a = iv dose only b = po dose only The blood samples were collected into heparinised tubes and then centrifuged at 3000 rpm for 10mins to produce plasma, which was deep-frozen at -2O⁰C prior to analysis by HPLC/MS/MS. The plasma samples were thawed at room temperature. Plasma samples, calibration standards and quality control samples (100μl) were transferred into a pyrex DVT culture tube using a Gilson pipette. Water (400μl) and 20μl of 1μg/ml 2(S)-2-aminomethyl-4-propyl heptanoic acid as an internal standard was added to each tube, followed by 500μl 1M mono-chloro acetic acid {MCA} (1 :9 v/v methanol/water). All tubes were vortex mixed for five seconds. 1 ml methanol and 1 ml 1 M MCA was added sequentially to the solid phase extraction (SPE) block, appropriate vacuum was applied at each step. Samples were loaded into the 96-well block using a plastic graduated pipette and appropriate vacuum applied. 1ml water, 1ml 1 M MCA and 1ml methanol were sequentially added to the SPE block and appropriate vacuum was applied at each step. 1ml 5% ammonia in methanol was added to the block and samples eluted into a 96-well collection plate. The eluent was evaporated to dryness by placing the 96 well block on the 96-well sample concentrator. 300μl of 2mM ammonium acetate in 10:90 methanol/water (MF3) is added to each well and the 96 well block is centrigued at 3000 rpm for 30 minutes. 180μl was injected onto the HPLC column for LC/MS/MS analysis.

The HPLC/MS/MS analysis was performed on a Sciex API 3000 mass spectrometer using the following chromatographic and MS conditions:

High Performance Liquid Chromatography - Mass Spectrometry (HPLC-MS)

HPLC pump:- Hewlett Packard HP1100 binary pump

Autosampler:- CTC Pal

Injection volume:- 180μl (2mM ammonium acetate in 10:90 methanol / water)

Mobile Phase:- 2mM ammonium acetate in 10:90 methanol/water (MF3) and 2mM ammonium acetate in 90:10 methanol/water (MF2) Gradient:-

Flowrate:- 3ml/min, split 5:1 post-column using an Acurate™ flow splitter Switching valve :- Valco 2 position valve, 0 to 0.41 min flow switched to waste 0.41 min to 2.2min flow switched to mass spectrometer

Column:- Chromolith speed rod RP-18e, 5cm by 4.6mm

Mass Spectrometer:- Sciex API 3000 with TurbolonSpray interface Detection mode:- Positive ion multiple reaction monitoring (MRM) lons monitored:- (2S)-2-aminornethyl-5-ethyl-heptanoic acid m/z 188>123 2(S)-2-aminomethyl-4-propyl heptanoic acid (internal standard) m/z 202>137

Q1 and Q3 resolution :- ca. 0.7 Da peak width at half-height Curtain gas:- Nitrogen at a setting of 12 (CUR) Nebuliser gas:- Nitrogen at a setting of 25 (GS1 ) TurbolonSpray gas:- Nitrogen at a setting of 40 (GS2) TurbolonSpray tempi- 100°C Collision gas:- Nitrogen at a setting of 2 Typical Voltages :- IS = 5.0 kV; RNG = 200V; QO = -10V; IQ1 = -11V; ST = -16; RO1 -11.5V;

MU = gain adjusted as per Sciex user manual; Dwell time:- 200msec, 50msec pause

The rat PK data are summarized in the table below.

Notes: a = the iv clearance of the racemate was estimated by taking the mean value for each of the enantiomers, assuming that each enantiomer does not affect the clearance of the other. This is believed to be a valid assumption as renal clearance is the predominant pathway involved. b = study was conducted at a dose of 3 mg/kg giving an AUC of 57 μg.h/ml, the data shown is dose normalized to 1 mg/kg. c = studies were conducted at a dose of 1 mg/kg. d = AUC is the area under the curve which is a measure of the total exposure of the animal to the compound between the time interval 0-z hours (where z = last measurable timepoint). Clearance (Cl) is calculated by dividing the dose administered by the total exposure after iv dosing and is expressed in units of ml/min/kg. Volume is calculated by dividing clearance by the elimination rate constant from the plasma concentration verses time plot (ie. V=CI/Kel). e = the predicted human half life is calculated using the rat iv clearance and volume.

Considering the rat PK parameters presented, an estimation of the elimination half-life in man can be predicted for each of the enantiomers and the racemate. Based on this data there is a three fold increase in predicted human half-life using (2S)-2-aminomethyl-5-ethyl-heptanoic acid compared to the racemate disclosed in WO-A-2003/082807.

There is a clear difference in the clearance of (2S)-2-aminomethyl-5-ethyl-heptanoic acid and the corresponding R-enantiomer, with the clearance of the latter being close to that which would be expected if cleared by passive renal glomerular filtration, whereas, (2S)-2-aminomethyl-5-ethyl- heptanoic acid appears to undergo active renal reabsorption resulting in a substantially lower clearance rate. This significant difference in renal clearance between the two enantiomers is thought to be due to an unexpected selective interaction with renal transporters.

Claims

1. (2S)-2-AminomethyI-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof.

2. (2S)-2-Aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

3. (2S)-2-Aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disease or condition for which an alpha-2-delta ligand is indicated.

4. (2S)-2-Aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, according to claim 3, wherein the disease or condition is pain.

5. Use of (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease or condition for which an alpha-2-delta ligand is indicated.

6. Use according to claim 5 wherein the disease or condition is pain.

7. A method of treating a disease or condition for which an alpha-2-delta ligand is indicated in a mammal, including a human being, comprising administering an effective amount of (2S)-2- aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof.

8. A method according to claim 7 wherein the disease or condition is pain.

9. A pharmaceutical composition comprising (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipient(s).

10. A combination of (2S)-2-aminomethyl-5-ethyl-heptanoic acid, or a pharmaceutically acceptable salt or solvate thereof, and one or more further pharmacologically active compounds.