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WO2007135530A2 - Sel adapté à un usage pharmaceutique et vétérinaire - Google Patents

Sel adapté à un usage pharmaceutique et vétérinaire Download PDF

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Publication number
WO2007135530A2
WO2007135530A2 PCT/IB2007/001296 IB2007001296W WO2007135530A2 WO 2007135530 A2 WO2007135530 A2 WO 2007135530A2 IB 2007001296 W IB2007001296 W IB 2007001296W WO 2007135530 A2 WO2007135530 A2 WO 2007135530A2
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WIPO (PCT)
Prior art keywords
urinary incontinence
pain
dichloro
pyrrolidin
cyclopentyl
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Ceased
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PCT/IB2007/001296
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WO2007135530A3 (fr
Inventor
Paul Vincent Fish
Florian Wakenhut
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Pfizer Ltd Great Britain
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Pfizer Ltd Great Britain
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Publication of WO2007135530A3 publication Critical patent/WO2007135530A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to an improved pharmaceutical and veterinarily acceptable salt of 2,3- dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide and compositions thereof.
  • the compound 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide exhibits activity as a serotonin and noradrenaline re-uptake inhibitor and therefore has utility in a variety of therapeutic areas.
  • this compound is of use in the treatment of disorders in which the regulation of monoamine transporter function is implicated, more particularly disorders in which inhibition of re-uptake of serotonin or noradrenaline is implicated.
  • this compound is of use in disorders in which inhibition of both serotonin and noradrenaline is implicated, such as urinary incontinence.
  • this compound is of use. in disorders in which it may be desired to inhibit preferentially the reuptake of one of noradrenaline or serotonin compared with the other, such as pain, fibromyalgia, ADHD and depression.
  • PXRD powder X-ray diffraction pattern
  • DSC differential scanning calorimetry
  • the invention provides a tablet formulation comprising the hemi-citrate salt of 2,3-dichloro-N- cyclopentyl-N-[(3S)-pyrrolidiri-3-yl]benzamide in admixture with excipients.
  • a preferred formulation includes the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide, a compression aid such as microcrystalline cellulose, an additive to provide sheen to the tablet such as anhydrous dibasic calcium phosphate, a disintegrant such as sodium starch glycollate and a lubricant such as magnesium stearate.
  • the invention provides a capsule formulation comprising the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]ben2amide in . admixture with excipients.
  • a preferred formulation includes the hemi-citrate salt, an inert diluent, a disintegrant and a lubricant as described above.
  • the invention further provides the hemi-citrate salt of 2,3-dichloro-N- cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide in sterile aqueous solution for parenteral administration.
  • such solution contains from 10 to 40% by volume of propylene glycol and preferably also sufficient sodium chloride to avoid haemolysis, e.g. about 1% w/v.
  • the hemi-citrate salt of 2,3-dichloro-/V-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide is useful because it has pharmacological activity in mammals, including humans.
  • it is useful in the treatment or prevention of disorders in which the regulation of monoamine transporter function is implicated, more particularly disorders in which inhibition of re-uptake of serotonin or noradrenaline is implicated, and especially those in which inhibition of serotonin and noradrenaline re-uptake is implicated.
  • the hemi-citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide is useful in the treatment of urinary incontinence, such as genuine stress incontinence (GSI), stress urinary incontinence (SUI) or urinary incontinence in the elderly; overactive bladder (OAB), including idiopathic detrusor instability, detrusor overactivity secondary to neurological diseases (e.g. Parkinson's disease, multiple sclerosis, spinal cord injury and stroke) and detrusor overactivity secondary to bladder outflow obstruction (e.g.
  • OAB benign prostatic hyperplasia
  • urethral stricture or stenosis urethral stricture or stenosis
  • nocturnal eneuresis urinary incontinence due to a combination of the above conditions (e.g. stress incontinence associated with overactive bladder); and lower urinary tract symptoms, such as frequency and urgency.
  • the term OAB is intended to encompass both OAB wet and OAB dry.
  • the hemi-citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide is also useful in the treatment of depression, such as major depression, recurrent depression, single episode depression, subsyndromal symptomatic depression, depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, paediatric depression, child abuse induced depression, depression in infertile women, post partum depression, premenstrual dysphoria and grumpy old man syndrome.
  • the hemi-citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide is also useful in the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; mild cognitive impairment associated with ageing, particularly age associated memory impairment (AAMI), amnestic disorder and age-related cognitive decline (ARCD); psychotic disorders, such as schizophrenia and mania; anxiety disorders, such as generalised anxiety disorder, phobias (e.g.
  • agoraphobia social phobia and simple phobias
  • panic disorder obsessive compulsive disorder
  • post traumatic stress disorder mixed anxiety and depression
  • personality disorders such as avoidant personality disorder and attention deficit hyperactivity disorder (ADHD)
  • sexual dysfunction such as premature ejaculation, male erectile dysfunction (MED) and female sexual dysfunction (FSD) (e.g.
  • FSAD female sexual arousal disorder
  • SAD seasonal affective disorder
  • eating disorders such as anorexia nervosa and bulimia nervosa
  • obesity appetite suppression
  • chemical dependencies resulting from addiction to drugs or substances of abuse such as addictions to nicotine, alcohol, cocaine, heroin, phenobarbital and benzodiazepines
  • withdrawal syndromes such as those that may arise from the aforementioed chemical dependencies
  • cephalic pain such as migraine, cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with chemical dependencies or withdrawal syndromes resulting from chemical dependencies, and tension headache
  • pain Parkinson's diseases, such as dementia in Parkinson's disease, neuroleptic- induced Parkinsonism and tardive dyskinesias
  • endocrine disorders such as hyperprolactinaemia
  • vasospasm such as in the cerebral vasculature
  • Tourette's syndrome Tourette's syndrome
  • ADHD is of particular interest.
  • the diagnosis of ADHD is based on clinical evaluation (M. Dulcan, et al. J Am Acad Child Adolesc Psychaitry, Oct. 1997, 36(10 Suppl), 85S-121S; National Institutes of Health, 1998).
  • "The essential feature of ADHD is a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparative level of development” (Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), American Psychiatric Association, Washington, D.C., 1994).
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • patients In order to be diagnosed with ADHD, patients must demonstrate symptoms of ADHD that cause impairment before the age of seven years, and symptoms must have been ongoing for longer than six months in at least two settings (e.g., school [or work] and home). (See DSM-IV).
  • the hemi-citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide is also useful in the treatment of a number of other conditions or disorders, including hypotension; gastrointestinal tract disorders (involving changes in motility and secretion) such as irritable bowel syndrome (IBS), ileus (e.g. post-operative ileus and ileus during sepsis), gastroparesis (e.g.
  • IBS irritable bowel syndrome
  • ileus e.g. post-operative ileus and ileus during sepsis
  • gastroparesis e.g.
  • GORD gastroesophageal reflux disease
  • NUD non-ulcerative dyspepsia
  • NCCP non-cardiac chest pain
  • the hemi-citrate salt of 2,3-dichioro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide is also useful in the treatment of pain.
  • 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 (non-myelinated).
  • A-delta fibres myelinated
  • C fibres non-myelinated
  • Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually in 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.
  • neuropathic pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • carpal tunnel syndrome e.g. painful diabetic neuropathy, postherpetic neuralgia
  • back pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • 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 a!., 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, postoperative 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.
  • 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 (Qrennan & Jayson, 1994, Textbook of Pain, 397-407).
  • 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.
  • Gl gastrointestinal
  • FBD functional bowel disorder
  • IBD inflammatory bowel disease
  • Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageai 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.
  • 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.
  • disorders of particular interest include urinary incontinence, such as mixed incontinence, GSI and SUI; pain; fybromyalgia; ADHD and depression.
  • the invention further provides the hemi-citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3- yl]benzamide for use in treating urinary incontinence, pain, fibromyalgia, ADHD, and depression in humans.
  • the invention further provides the hemi-citrate salt of 2,3-dichloro- ⁇ /- cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide for use in the treatment of urinary incontinence, such as genuine stress incontinence (GSI), stress urinary incontinence (SUI) or urinary incontinence in the elderly; overactive bladder (OAB), including idiopathic detrusor instability, detrusor overactivity secondary to neurological diseases (e.g. Parkinson's disease, multiple sclerosis, spinal cord injury and stroke) and detrusor overactivity secondary to bladder outflow obstruction (e.g.
  • the term OAB is intended to encompass both OAB wet and OAB dry.
  • the invention further provides the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)- pyrrolidin-3-yl]benzamide for use in treating urinary incontinence in animals, particularly dogs.
  • the invention also provides a process for preparing the hemi-citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl-/V- [(3S)-pyrrolidin-3-yl]benzamide by reacting 2,3-dichloro- ⁇ /-cyclopentyl-/V-t(3S)-pyrrolidin-3-yl]benzamide with citric acid in an inert solvent and recovering the hemi-citrate salt.
  • the preferred inert solvent is is isopropyl alcohol (IPA).
  • the present invention also includes all suitable isotopic variations of the hemi-citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide.
  • An isotopic variation of the hemi-citrate salt of 2,3- dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide is defined as one in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the hemi-citrate salt of 2,3- dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide include isotopes of hydrogen, carbon, nitrogen and oxygen such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O and 18 O respectively.
  • Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e. 2 H, 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.
  • isotopic variations of the hemi-citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide can generally be prepared by conventional procedures such as those described in the following examples and preparations using appropriate isotopic variations of suitable reagents.
  • 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide is effective in its free base form, in practice, for formulation purposes, it is best administered in the form of asalt of a pharmaceutically and/or veterinarily acceptable acid.
  • 2,3- dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyPr ⁇ lidi ⁇ : 3 " -yl]benzamide have been identified.
  • acid addition salts containing pharmaceutically and/or veterinarily acceptable anions such as the hydrochloride, hydrobromide, hemi-ethane-1 ,2-disulfonate (hemi-edisylate), ethane-1 ,2-disulfonate (edisylate), fumarate, D-tartrate, L-tartrate, acetate and hemi-sulfate salts have been found suitable.
  • the hemi- citrate salt of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide has a number of advantages which make it particularly suitable for the preparation of pharmaceutical formulations of 2,3-dichloro- ⁇ /- cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide.
  • Salts over which the compound of the invention has been found to have formulation advantages include: the hydrochloride, hydrobromide, hemi-edisylate, . edisylate, fumarate, L-tartrate, D-tartrate, acetate and hemi-sulfate.
  • the hemi-edisylate may be prepared in accordance with the method disclosed at Example 1 in International Patent Application PCT/IB05/003643 (which published as WO 2006/056884 on 1 st June 2006). Additional salts of 2,3- dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide can be prepared in accordance with such methods as are known in the art for the manufacture of acid addition salts, or in accordance with the methods detailed hereinafter (at Examples 3 to 11).
  • alternative salts of 2,3-dichloro- ⁇ /- cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide may be readily prepared by mixing together solutions of the compound and the, desired acid or base, as appropriate.
  • Such alternative salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • Table 1 illustrates a selection of the advantageous combination of formulation properties of the salt form according to the present invention [Example 2], including non-hygroscopicity and non-solvated..
  • Tables 2A and 2B illustrates the results of laboratory scale studies of a selection of the formulation properties of the salt form according to the present invention [Example 2A] in comparison to other salt forms.
  • Tables 2A and 2B illustrate that, of all the salts tested, only the hemi-citrate salt of 2,3-dichloro- ⁇ /- cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide exhibits the advantageous combination of attributes: desired crystallinity; a single, sharp endotherm; and being non-solvated.
  • the thermal results are positive as higher melting points are desirable for ease of processing.
  • the compound of the invention may be administered alone or as part of a combination therapy. If a combination of therapeutic agents is administered, then the active ingredients may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • Suitable agents for adjunctive therapy include:
  • 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;
  • NSAID nonsteroidal antiinflammatory drug
  • NSAID nonsteroidal antiinflammatory drug
  • 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
  • NSAID nonsteroidal antiinflammatory drug
  • 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 H 1 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.
  • 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
  • doxazosin tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, phentolamine, terazasin, prazasin 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.
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g. ( ⁇ R,9R)-7-[3,5- bis(trifluoromethyl)benzyl]-8,9,10,11 -tetrahydro-9-methyl-5-(4-methylphenyl)-7H-
  • NK tachykinin
  • 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)
  • 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 -fl[1 ,2,4]triazin-4-one (varden
  • [1 ,2,4]oxadiazol-5-one C-[1 -(1 H-tetrazol- ⁇ -ylmethyO-cycloheptyll-methylamine, (3S,4S)-(1 - aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic 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, granisetron, tropisetron, azasetron, dolasetron or alosetron;
  • an oestrogen agonist or selective oestrogen receptor modulator e.g. HRT therapies or lasofoxifene
  • an alpha-adrenergic receptor agonist such as phenylpropanolamine or R-450
  • a dopamine receptor agonist e.g. apomorphine, teachings on the use of which as a pharmaceutical may be found in US-A-5945117
  • a dopamine D2 receptor agonist e.g. premiprixal, Pharmacia Upjohn compound number PNU95666; or ropinirole
  • a PGE1 agonist e.g. alprostadil
  • the invention thus provides, in a further aspect, a combination comprising the hemi-citrate salt of 2,3- dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide together with a further therapeutic agent.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrro!idin-3-yljbenzamide can be administered alone, but in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate- , delayed-, modified-, sustained-, dual-, controlled-release or pulsatile delivery applications.
  • the the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide may also be administered via intracavemosal injection.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3- yl]benzamide may also be administered via fast dispersing or fast dissolving dosage forms.
  • Such tablets may contain excipients such as micro-crystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • excipients such as micro-crystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates,
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compounds of the invention, and their pharmaceutically acceptable salts may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device.
  • Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacryli ⁇ acid copolymer and mixtures thereof.
  • Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients.
  • Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.
  • Fast dispersing or dissolving dosage formulations may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
  • dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneal ⁇ , intrathecal ⁇ , intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the daily dosage level of the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide will usually be from 10 to 500 mg (in single or divided doses).
  • tablets or capsules of the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)- pyrrolidin-3-yl]benzamide thereof may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide may be taken as a single dose on an "as required" basis (i.e. as needed or desired).
  • a tablet formulation could typically contain between about 0.01 mg and 500mg of of the hemi- citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-y ⁇ ]benzamide whilst tablet fill weights may range from 50mg to 1000mg.
  • An example formulation for a 10mg tablet is illustrated:
  • This quantity is typically adjusted in accordance with drug activity and is based on the weight of the free base.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide can also be administered intranasally or by inhalation and may be conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebulizer with the use of a suitable propellant, e.g.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff" contains from 1 to 50 mg of of the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide may also be formulated for delivery via an atomiser.
  • Formulations for atomiser devices may contain the following ingredients as solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the hemi-citrate salt of 2,3-dichloro-N- cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide may also be dermally or transdermal ⁇ administered, for example, by the use of a skin patch.
  • the compound may also be administered by the ocular, pulmonary or rectal routes.
  • the compound can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
  • the compound may be formulated in an ointment such as petrolatum.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3- yl]benzamide can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene. compound, emulsifying wax.and water.
  • the compound can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide may also be used in combination with a cyclodextrin.
  • Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule.
  • Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, e.g.
  • Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A- 91/11172, WO-A-94/02518 and WO-A-98/55148.
  • the daily dosage levels of compound will be from 0.01 to 30 mg/kg (in single or divided doses) and preferably will be in the range 0.01 to 5 mg/kg.
  • tablets will contain 1mg to 0.4g of compound for administration singly or two or more at a time, as appropriate.
  • the physician will in any event determine the actual dosage which will be most suitable for any particular patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are, of course only exemplary of the average case and there may be instances where higher or lower doses are merited, and such are within the scope of-the invention.
  • Oral administration is preferred.
  • the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
  • the invention provides a pharmaceutical formulation containing of the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable adjuvant, diluent or carrier comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • " * ' "' When the hemi-citrate salt of 2,3-dichloro-N-cyclopentyl-N-[(3S)-pyrroliclin-3-yl]benzamide is used in combination with a second therapeutic the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • Figure 1 Calculated Powder X-ray Diffraction Pattern of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3- yl]benzamide hemi-citrate.
  • Figure 2 Measured Powder X-ray Diffraction Pattern of 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3- yljbenzamide hemi-citrate, Sample A [Example 2A] (using a Bruker-AXS ltd D5000 powder X-ray diffractometer)
  • 2,3-dichloro- ⁇ /-cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide may be prepared by the methods disclosed in International Patent Application Publication Number WO2004/110995 and International Patent Application Number PCT/IB05/003643 (which published as WO 2006/056884 on 1 st June 2006), or as described below:
  • Flash column chromatography was carried out using Merck silica gel 60 (9385). Solid Phase Extraction (SPE) chromatography was carried out using Varian Mega Bond Elut (Si) cartridges (Anachem) under 15mmHg vacuum. Thin layer chromatography (TLC) was carried out on Merck silica gel 60 plates (5729). Melting points were determined using a Gallenkamp MPD350 apparatus and are uncorrected. NMR was carried out using a Varian-Unity Inova 300MHz and 400MHz Nmr spectrometers or a Varian Mercury 400MHz nmr spectrometer.
  • aqueous solution pH was adjusted to below 6 with 2N HCI (aq) and then washed with TBME (7.52L) and the organic phase separated and discarded.
  • the aqueous phase was cooled to 5 0 C and basified with aqueous potassium carbonate (6.63kg, 48 mole in water 7.52L) and the product extracted with dichloromethane (DCM) (3 x 18.8L).
  • DCM dichloromethane
  • the combined DCM layers were washed with water (7.52L) and the solvent distilled and replaced under vacuum with iso-propyl alcohol (IPA) (31.3L) to give an IPA solution of the title compound in approximately 15L IPA (5.81 kg product, 31.2 mole, 71%)
  • cyclopentanone (12.7ml, 143mmol) was added to tert- butyl (3S)-3-aminopyrrolidine-1-carboxylate (26.6g, 143mmol) in a mixture of methanoktoluene 3:1 (600m I: :200m I), and the reaction mixture was stirred at room temperature for 1.5 hours, under nitrogen. The reaction mixture was then evaporated to 50ml, azeotroped three times with methanoktoluene 3:1 (600ml:200ml) and concentrated in vacuo.
  • the resultant mixture was allowed to warm to room temperature at stirred for a minimum of 5 hours upon which the phases were separated.
  • the organic phase was washed with hydrochloric acid ([1 M]), 31.4L, 31.4mole) and water (31.4L) and then azeotropically dried by the addition and distillation of a further portionjpf toluene (20L) at reduced pressure.
  • the title product was held as a toluene solution (38.25kg of solution containing 10.4kgA product, 24.3mole, 99%).
  • Example 1 A Alternative preparation of 2,3-dichloro- ⁇ E-cvclopentyl- ⁇ HT3S)-pyrrolidin-3- ylibenzamide
  • Toluene (4.4L) was added to the previously described solution of tert-butyl (3S)-3-[cyclopentyl(2,3- dichlorobenzoyl)amino]pyrrolidine-1-carboxylate (of Preparation 4A) in toluene and the solution was cooled to 0 0 C.
  • Trifluoroaceitic acid (TFA) 13.85 kg, 121.5mole, 5 equiv. was added at such a rate as to maintain the temperature below 15 0 C, and the line rinsed in with toluene (5L). The reaction mixture was heated to 45 0 C for 3 hours.
  • the combined acidic aqueous phase was washed with toluene (10.4L) and then basified to greater than pH 9 with aqueous sodium hydroxide ([5M], 10.4L, 52mole).
  • the aqueous phase was extracted with TBME (2 x 31.2L) and the combined organic phase washed with water (20.8L).
  • the TBME was distilled and replaced to IPA under reduced pressure (2 x 20L) to give the title compound as an IPA solution (26.2kg of solution, 6.95kgA of product, 21.2mole, 87%).
  • a solution of citric acid (2.04kg, 0.5 equivalents) in water (2L) was added to a solution of 2,3-dichloro- ⁇ /- cyclopentyl- ⁇ /-[(3S)-pyrrolidin-3-yl]benzamide free base (6.95kg, 1 equivalent) in isopropyl alcohol (35L) at such a rate that the internal temperature did not rise above 25 0 C.
  • the resultant slurry was stirred at 25 0 C for 2 hours after which it was filtered.
  • the filter 4 cake was pulled dry and washed with isopropyl alcohol (20.8L) and again pulled as dry as possible.
  • the relative intensities of the various peaks within the given tables may vary due to a number of factors such as, for example, orientation effects of crystals in the X-ray beam, or the purity of the material being analysed, or the degree of crystaUinity of the sample.
  • the peak positions may also shift for variations in sample height, but the peak positions will remain substantially as defined in the given tables.
  • Such further PXRD patterns generated by use of alternative wavelengths are considered to be alternative representations of the PXRD patterns of the crystalline materials of the present invention and as such are within the scope of the present invention.
  • the DSC thermogram ( Figure 4) was generated from a 2.382mg sample of 2,3-dichloro- ⁇ /-eyclopentyl- ⁇ /- [(3S)-pyrrolidin-3-yl] benzamide hemi-citrate [Sample A] in an aluminium pan with lid using a TA Instruments Q1000 differential scanning calorimeter. The sample was heated from 30-300 0 C at a rate of 20°C/min. in a nitrogen furnace atmosphere purged at 50 cm 3 /min. A sharp melt endotherm peak was seen at 206°, followed by multiple degradation events.
  • the DSC thermogram ( Figure 5) was generated from a 3.008mg sample of 2,3-dichloro-/V- cyclopentyl ⁇ /-[(3S)-pyrrolidin-3-yl] benzamide hemi-citrate [Sample B] in an aluminium vented pan using a Perkin Elmer Diamond differential scanning calorimeter.
  • the sample was heated from ambient-300°C at a rate of 20°C/min. in a nitrogen furnace atmosphere purged at 40 cm 3 /min. A melt endotherm peak was seen at 213°, followed by multiple degradation events.
  • Example 1 exhibited an NRI Ki of 15 nM and an SRI Ki of 5nM.
  • the NRI Ki and the SRI Ki of the compounds of the Examples therein were determined as follows.
  • the compounds were tested for biological activity by their ability to inhibit binding of selective radioligands at the human serotonin and noradrenaline transporters (SERT and NET, respectively), using scintillation proximity assay (SPA) technology.
  • the SPA binding was performed using cellular membrane preparations prepared from cell lines expressing human cDNA encoding either SERT or NET (hSERT, hNET), using the radioligands 3 H-citalopram and 3 H-nisoxetine.
  • Human embryonic kidney cells (HEK-293) expressing each transporter were maintained as a continuous culture, using standard cell culture techniques, in 50 mL of growth medium (see Media and Buffers for composition) in 225 cm 2 flasks, at 37 2 C in a humidified atmosphere with 5 % CO 2 present. Cells were passaged from a 90 % confluent monolayer at a ratio of 1 :3 - 1 :4.
  • the growth medium was removed from the monolayer and. the cells were, incubated with cell dissociation solution (Sigma) until showing signs of dissociation. The cells were subsequently knocked from the base of the flask and pelleted by centrifugation for storage (frozen at - 80 S C) prior to further use.
  • Cell pellets were thawed on ice and resuspended in 3 mL of membrane preparation buffer (see Media and Buffers for composition) per 1 mL of packed cell volume, using a vortex mixer to disperse the cell pellet.
  • the suspension was homogenised for four individual 10 second intervals using a hand-held homogeniser.
  • the homogenate was then centrifuged at 1075 x g for 20 minutes at 4 a C.
  • the pooled supernatants were . centrifuged at 35000 x g for 30 minutes at 4 2 C, and the supernatants discarded. The pellets (P2) were then resuspended in 1 mL of membrane preparation buffer per 1 mL of the original packed cell volume. Protein concentrations were then measured and the membrane suspension was finally frozen in aliquots of set volume and stored at - 80 2 C prior to use in assays.
  • SPA bead type differed for each transporter, wheat germ agglutinin-coated yttrium silicate (YSi WGA) SPA beads were used for hSERT and WGA-coated polyvinyltoluene (PVT WGA) SPA beads for hNET assays. For each batch of membrane used, optimal concentrations of bead and membrane were determined
  • Tritiated radioligands specific to each transporter 3 H-citalopram for rtSERT and 3 H-nisoxetine for hNET were used.
  • the assay free radioligand concentration was expressed as a percentage of the total free radioligand concentration to give an estimate of the radioligand depletion.
  • the radioligand depletion in assays for both transporters was less than 30% to ensure that there was sufficient radioligand available for binding.
  • the ligand depletion value was also used for selecting the optimal assay conditions when using new batches of membranes.
  • the affinity of the specific radioligand for the respective transporter was determined for each membrane batch at the selected protein and bead concentrations. This was achieved by the determination of the K D , the concentration of free radioligand at which 50 % of the transporter binding sites were occupied.
  • the mean K D for a radioligand at a batch of membranes was determined from data from a rjninimum of three separate assays. The mean K D was subsequently used for all assays using the membrane batch profiled to enable determination of K 1 values of compounds studied using the method determined by Cheng and Prussoff (Cheng YC and Prusoff WH. Relationship between the inhibition constant (K 1 ) and the concentration of inhibitor which causes 50% inhibition of an enzymatic reaction. Biochem Pharmacol 1973; 22:2099-3108.)
  • test compounds were prepared at a concentration of 4 mM in 100 % dimethyl sulphoxide (DMSO) from dry samples. Compounds were diluted in 0.75 % DMSO in ddH 2 O to give appropriate test concentrations in a 384 well plate to give a final volume of 20 ⁇ l_.
  • DMSO dimethyl sulphoxide
  • the assay window (specific binding) per plate was calculated by subtracting the mean NSB readings (in counts per minute, or cpm) from the mean of total binding readings. Subsequently the cpm read per well
  • the inhibitory dissociation constant (K 1 ) value was then calculated from the IC 50 value using the Cheng-

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Abstract

Un sel amélioré acceptable au niveau pharmaceutique et vétérinaire de 2,3-dichloro-Ν-cyclopentyl-Ν-[(3S)- pyrrolidin-3-yl]benzamide et des compositions de celui-ci, est décrit.
PCT/IB2007/001296 2006-05-22 2007-05-10 Sel adapté à un usage pharmaceutique et vétérinaire Ceased WO2007135530A2 (fr)

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