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WO2009112541A2 - [2-(6-fluoro-1h-indol-3-ylsulfanyl)benzyl]méthyl amine pour le traitement des troubles de l’humeur - Google Patents

[2-(6-fluoro-1h-indol-3-ylsulfanyl)benzyl]méthyl amine pour le traitement des troubles de l’humeur Download PDF

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Publication number
WO2009112541A2
WO2009112541A2 PCT/EP2009/052899 EP2009052899W WO2009112541A2 WO 2009112541 A2 WO2009112541 A2 WO 2009112541A2 EP 2009052899 W EP2009052899 W EP 2009052899W WO 2009112541 A2 WO2009112541 A2 WO 2009112541A2
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Prior art keywords
pain
disorder
depression
syndrome
sleep
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Ceased
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WO2009112541A3 (fr
Inventor
Jeffrey Scott Sprouse
Karina Krøjer SØBY
Neil Anderson
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H Lundbeck AS
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H Lundbeck AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • Field of the invention provides therapeutic treatment of CNS diseases.
  • Sleep is a vital factor in many affective disorders, such as e.g. depression and anxiety.
  • sleep disruption is a major symptom of depression, and often it is the sleep disruption that causes a patient suffering from depression to seek help.
  • any medical intervention offered to the patient ameliorates the sleep disturbances and, certainly, that it does not itself add to the sleep problems. The same, of course, holds true for the treatment of other affective disorders.
  • Standard medical treatment of affective disorders includes compounds having the effect of increasing the level of the monoamine neurotransmitters serotonin and/or noradrenalin in the brain.
  • these medicaments are used for the treatment of a wide variety of affective disorders, they are normally referred to as "antidepressants".
  • the most widespread treatment modalities include selective serotonin reuptake inhibitors (SSRI) which increase the level of serotonin, well-known and marketed examples of which include escitalopram, fluoxetine and sertraline.
  • SSRI selective serotonin reuptake inhibitors
  • NRI selective noradrenalin reuptake inhibitors
  • noradrenalin one example of which is reboxetine.
  • TCA tri-cyclic antidepressant
  • noradrenalin reuptake inhibitory effects brings about an increase in the level of noradrenalin, which is the cause of the therapeutic effect in the treatment of affective disorders.
  • Noradrenalin also has peripheral effects, e.g. increased heart rate, blood vessel constriction and a consequent increase in blood pressure.
  • the present inventors have surprisingly found that [2-(6-fluoro-lH-indol-3- ylsulfanyl)benzyl]methyl amine is a potent serotonin reuptake inhibitor, a potent noradrenalin reuptake inhibitor, and a potent CC IA receptor antagonist, and as such useful in the treatment of CNS disorders. Accordingly, in one embodiment, the invention relates to methods of treatment, the method comprising the administration of a therapeutically effective amount of
  • the invention relates to [2-(6-fluoro-lH-indol-3- ylsulfanyl)benzyl]methyl amine or a pharmaceutically acceptable salt thereof (compound I) for use in the treatment of diseases.
  • the invention relates to the use of [2-(6-fluoro-lH-indol-3- ylsulfanyl)benzyl]methyl amine or a pharmaceutically acceptable salt thereof (compound I) in the manufacture of a medicament.
  • Figure 1 X-ray powder diffractogram of the CC form of the L(+) hydrogen tatrate salt
  • Figure 2 X-ray powder diffractogram of the ⁇ form of the L(+) hydrogen tatrate salt
  • the present invention relates to the use of [2-(6-fluoro-lH-indol-3-ylsulfanyl)benzyl]methyl amine and pharmaceutically acceptable salts thereof (compound I).
  • said pharmaceutically acceptable salts are acid addition salts of acids that are non-toxic.
  • Said salts include salts made from organic acids, such as sabaconic, 2- hydroxy isobutyric, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • Said salts may also be made from inorganic salts, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Particular mentioning is made of salts made from methanesulfonic acid, maleic acid, fumaric acid, meso-tartaric acid, (+)-tartaric acid, (-)-tartaric acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphorous acid and nitric acid. Distinct mention is made of the L-(+)-hydrogen tatrate salt. Oral dosage forms, and in particular tablets or capsules, are often preferred by the patients and the medical practitioner due to the ease of administration and the consequent better compliance.
  • the active ingredients are crystalline.
  • the compounds used in the present invention are crystalline.
  • the crystals used in the present invention are solvates, i.e. crystals wherein solvent molecules form part of the crystal structure.
  • the solvate may be formed from water, in which case the solvates are often referred to as hydrates.
  • the solvates may be formed from other solvents, such as e.g. ethanol, acetone, or ethyl acetate.
  • the exact amount of solvate often depends on the conditions. For instance, hydrates will typically loose water as the temperature is increased or as the relative humidity is decreased.
  • the compounds used in the present invention are not solvates.
  • crystals are well-defined.
  • the term "well-defined” in particular means that the stoichiometry is well-defined, i.e. that the ratio between the ions forming the salt is the ratio between small integers, such as 1:1, 1:2, 2:1, 1 :1 :1, etc.
  • the compounds used in the present invention are well-defined crystals.
  • Some compounds may be hygroscopic, i.e. absorb water when exposed to humidity.
  • Hygroscopicity is generally regarded as an undesired property for compounds that are to be presented in a pharmaceutical formulation, in particular in a dry formulation, such as tablets or caplsules.
  • the invention uses crystals with low hygroscopicity.
  • the solubility of an active ingredient is also of significance for the choice of dosage form as it may have a direct impact on bio-availability.
  • a higher solubility of the active ingredient is generally believed to be beneficial as it increases the bioavailability.
  • Some patients, e.g. elderly patients may have difficulties swallowing tablets, and oral drop solutions may be a suitable alternative avoiding the need for swallowing tablets.
  • oral drop solutions may be a suitable alternative avoiding the need for swallowing tablets.
  • the crystalline compounds of the present invention may exist in more than one form, i.e. they may exist in polymorphic forms. Polymorphic forms exist if a compound can crystallize in more than one form. The present invention is intended to encompass the use of all such polymorphic forms, either as pure compounds or as mixtures thereof.
  • the invention uses crystalline forms of [2-(6-fluoro-lH-indol-3-ylsulfanyl)benzyl]methyl amine L- (+) hydrogen tatrate which exists in two polymorphic forms, the CC form and the ⁇ form.
  • the XRPD of the CC form and the ⁇ form are shown in figures 1 and 2, respectively.
  • the cc form has a higher melting point and a lower solubility and is therefore expected to be a more stable form than the ⁇ form.
  • the invention uses the CC form of [2-(6-fluoro-lH-indol-3-ylsulfanyl)benzyl]methyl amine L-(+) hydrogen tatrate.
  • the invention uses crystalline forms of [2-(6- fluoro-lH-indol-3-ylsulfanyl)benzyl]methyl amine L-(+) hydrogen tatrate with an XRPD with major peaks at around 9.66, 14.53, 18.14 and 30.48 (°2 ⁇ ).
  • the invention uses crystalline forms of [2-(6-fluoro-lH-indol-3-ylsulfanyl)benzyl]methyl amine L- (+) hydrogen tatrate with an XRPD as depicted in Figure 1.
  • Sleep quality may be quantified subjectively, i.e. the subject at interest scores himself or is being scored on relevant parameters describing how the sleep is perceived.
  • Clinical scores used include HAS, HRSD and the Pittsburgh Sleep Quality Index.
  • objective information may be obtained by measuring brain activity (electroencephalography, EEG), muscle activity (electromyography, EMG), or observing physiological parameters, such as eye movement.
  • EEG electronic electroencephalography
  • EMG electromyography
  • eye movement Using objective quantification of sleep, two types of sleep, i.e. REM and non-REM sleep have been defined in mammals, and indeed in humans.
  • REM Rapid Eye Movement
  • sleep is defined by fast and low voltage brain waves (as measured by EEG) similar to the awake state, and irregular autonomic activities, such as heart rate and respiration.
  • Non-REM sleep is defined by slow and high voltage brain waves and the autonomic activities, such as heart rate and blood pressure, being low and regular.
  • Non-REM sleep is a deep and dreamless type of sleep. It is thought that certain restorative processes take place during the non-REM sleep, for instance growth hormone is being released during this type of sleep.
  • Stage 1 shows a slowing of EEG activities and is the transition from drowsiness to light sleep.
  • Stage 2 shows an emergence of sleep spindles and K-complex wave forms.
  • Stage 3 and 4 are characterised by slow waves and are of deep sleep.
  • Stage 5 is the REM sleep.
  • Stage 3 and stage 4 are often referred to as slow wave sleep or SWS.
  • SWS slow wave sleep
  • the pattern varies from person to person, but typically consists of 4-5 cycles during the night.
  • the cycles change in the course of the night, so that most of the deep sleep (stages 3 and 4) takes place during the first half of the night and most of the REM sleep takes place in the second half of the night.
  • the average adult will experience that 80 % of the sleep is non-REM sleep and 20% of the sleep is REM sleep.
  • the patterns of occurrences of the various stages of sleep during the night is referred to as the sleep architecture.
  • An improvement of sleep or a lack of adverse sleep effects associated with a therapeutic intervention is ultimately judged by how the sleep quality is perceived by the patient.
  • parameters such as sleep latency (time before sleep occurs), number of awakenings during the night, sleep latency if awakened, the feeling of being rested and refreshed in the morning, insomnia, sleep duration, sleep sufficiency, early morning awakening, next day performance, and excessive daytime sleepiness are important for how an individual perceives his sleep.
  • sleep latency time before sleep occurs
  • sleep latency if awakened the feeling of being rested and refreshed in the morning
  • insomnia sleep duration
  • sleep sufficiency early morning awakening, next day performance
  • excessive daytime sleepiness are important for how an individual perceives his sleep.
  • compounds used in the present invention increase the amount of slow wave sleep, decreases the amount of REM sleep and decrease the sleep latency in a dose dependent manner in rats. These pre-clinical finding are expected to translate into improved sleep quality for patients who are being administered said compounds. As compounds having a combined inhibitory effect on the serotonin and noradrenaline uptake would prima facia be expected to reduce sleep quality, this is an unexpected result.
  • Increased blood pressure may give rise to dizziness and drowsiness, but often a subject suffering from increased blood pressure is not aware of his situation because there are no immediate or severe symptoms. Nevertheless, it is important to avoid even slightly increased blood pressure, as it is likely to have consequences, such as myocardial infarct, heart insufficiency, renal insufficiency and cerebral haemorrhage, in the long term.
  • Blood pressure is normally stated as the diastolic and the systolic blood pressure.
  • the systolic blood pressure is the pressure when the heart is fully contracted whereas the diastolic blood pressure is the pressure when the heart is fully relaxed.
  • Blood pressure is typically measured rested and supine, i.e. when the subject is lying down.
  • the average healthy subject will have a diastolic/systolic blood pressure of 80-90/130-140 mm Hg.
  • Bipolar disorder was formerly known as manic-depressive illness and it is characterised by recurrent episodes of mania and depression. Typically manic episodes are treated with antipsychotics, such as quetiapine or olanzapine, both of which exhibit 5-HT 2 A antagonistic effects or with lithium.
  • antipsychotics such as quetiapine or olanzapine, both of which exhibit 5-HT 2 A antagonistic effects or with lithium.
  • the compounds used in the present invention show antimanic effect which in the combination with the antidepressant properties suggest a use in the treatment of bipolar disorder, e.g. treatment of (hypo)manic episodes, treatment of major depressive episodes in the framework of bipolar disorder (bipolar depression), mood-stabilization of bipolar disorder, maintenance treatment of bipolar disorder, and recurrence prevention of bipolar disorder.
  • compound (I) may also be used in the treatment of pain, c/ " the use of TCA' s in pain treatment.
  • pain is or is associated with whiplash, IBS, chronic pain, phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex regional pain syndrome (CPRS), trigeminal neuralgia, trigeminus neuralgia, tic douloureux, pain after surgical intervention (e.g.
  • diabetic vasculopathy capillary resistance
  • diabetic symptoms associated with insulitis pain associated with menstruation
  • pain associated with cancer dental pain, headache, migraine, tension-type headache, temporomandibular joint syndrome, myofascial pain, muscular injury, bone and joint pain (osteoarthritis), rheumatoid arthritis, edema resulting from trauma associated with burns, osteoporosis, bone metastases, gout, f ⁇ brositis, thoracic outlet syndromes, pelvic pain, cardiac chest pain, non-cardiac chest pain, spinal cord injury (SCI)-associated pain, central post-stroke pain, cancer neuropathy, AIDS, sickle cell pain or geriatric pain.
  • SCI spinal cord injury
  • a segment of depressed patients will respond to treatment with e.g. SSRI in the sense that they will improve on clinically relevant depression scales, such as MADRS and HAMD, but where other symptoms, such as sleep disturbances and cognitive impairment remain.
  • these patients are referred to as partial responders.
  • compound I Due to the above discussed effects on the sleep quality, compound I is expected to be useful in the treatment of the partial responders, or rephrased that treatment of depressed patients with compound I will reduce the fraction of partial responders. Due to the pharmacological profile of the compounds used in the present invention, they are useful for the treatment of diseases which will benefit from an increase in the serotonin and/or noradrenalin levels in the brain.
  • the invention relates to a method of treating a diseases which will benefit from an increase in the serotonin and/or noradrenalin levels in the brain, the method comprising administering a therapeutically effective amount of compound I to a patient in need thereof.
  • said treatment is associated with little or no adverse sleep effects or an improvement of the sleep quality of the patient and/or with reduced or no cardiovascular side effects, such as increased blood pressure.
  • the invention provides a method for the treatment of mania, hypomania, bipolar disorder (maintenance), recurrence prevention of bipolar disorder, stabilization of bipolar disorder, depression in partial responders; treatment resistant depression; severe depression; cyclothymia; mood disorder due to a generalised medical condition; substance induced depression; recurrent depression; single episode depression; paediatric depression; atypical depression; post-stroke depression; exhaustion depression; seasonal affective disorder (SAD); depression associated with schizophrenia, schizoaffective disorder, gastrointestinal pain, IBS, abuse, hostility, irritability, fatigue, anxiety (anxious depression), Lewy Body disease, or multiple sclerosis; fear of flying, elevators or small rooms; general anxiety disorder associated with pain; anxiety in patients with increased risk of hypertension; anxiety in patients with sleep problems; cognitive impairment, Alzheimer's disease, dementia; mild cognitive impairment (MCI); vascular dementia; leucariosis; small vessel disease; compulsive and attention spectrum disorder associated with ADHD, Asperger's syndrome;
  • the patient to be treated suffers from a sleep related disorder. In one embodiment, the patient to be treated suffers from or is in the risk of suffering from hypertension. In one embodiment, the invention comprises an initial step of determining whether said patient suffers from or is in the risk of suffering from increased blood pressure or sleep related disorders, and wherein only patients who do not suffer from or is in the risk of suffering from increased blood pressure or sleep related disorders receive the medical treatment described above. In one embodiment, the present invention provides second line treatment for patients who cannot use other drugs, e.g. an antidepressant, such as SSRTs, SNRTs, NRTs, or TCA's, due to sleep or blood pressure related adverse effects.
  • an antidepressant such as SSRTs, SNRTs, NRTs, or TCA's
  • the patient to be treated has previously received another medication (or is still receiving it), which medication was ceased (or has to be ceased) due to sleep or blood pressure related adverse effects.
  • a “therapeutically effective amount” of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder comprising the administration of a compound of the present invention.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects of the invention.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • compound I is administered in an amount of from about 0.001 to about 100 mg/kg body weight per day.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical oral dosage for adults is in the range of 0.1-50 mg/day of a compound I, such as 0.5-30 mg/day, or 0.5-25 mg/day. This may typically be achieved by the administration of 0.1-50 mg, such as 0.5-30 mg, such as 0.5, 1, 2, 3, 4, 5, 6, 9, 10, 20 or 30 mg of the compound used in the present invention.
  • the treatment of the present invention will involve daily administration of the compounds of the present invention. This may involve once daily administration, or administration twice a day or even more frequently.
  • the invention relates to the use of compound I in the manufacture of a medicament for the treatment of mania, hypomania, bipolar disorder (maintenance), recurrence prevention of bipolar disorder, stabilization of bipolar disorder, depression in partial responders; treatment resistant depression; severe depression; cyclothymia; mood disorder due to a generalised medical condition; substance induced depression; recurrent depression; single episode depression; paediatric depression; atypical depression; post-stroke depression; exhaustion depression; seasonal affective disorder (SAD); depression associated with schizophrenia, schizoaffective disorder, gastrointestinal pain, IBS, abuse, hostility, irritability, fatigue, anxiety (anxious depression), Lewy Body disease, or multiple sclerosis; fear of flying, elevators or small rooms; general anxiety disorder associated with pain; anxiety in patients with increased risk of hypertension; anxiety in patients with sleep problems; cognitive impairment, Alzheimer's disease, dementia; mild cognitive impairment (MCI); vascular dementia; leucariosis; small vessel disease; compulsive and attention spectrum disorder
  • the invention relates to compound I for use in the treatment of mania, hypomania, bipolar disorder (maintenance), recurrence prevention of bipolar disorder, stabilization of bipolar disorder, depression in partial responders; treatment resistant depression; severe depression; cyclothymia; mood disorder due to a generalised medical condition; substance induced depression; recurrent depression; single episode depression; paediatric depression; atypical depression; post-stroke depression; exhaustion depression; seasonal affective disorder (SAD); depression associated with schizophrenia, schizoaffective disorder, gastrointestinal pain, IBS, abuse, hostility, irritability, fatigue, anxiety (anxious depression), Lewy Body disease, or multiple sclerosis; fear of flying, elevators or small rooms; general anxiety disorder associated with pain; anxiety in patients with increased risk of hypertension; anxiety in patients with sleep problems; cognitive impairment, Alzheimer's disease, dementia; mild cognitive impairment (MCI); vascular dementia; leucariosis; small vessel disease; compulsive and attention spectrum disorder associated with ADHD, Asperger'
  • Compound I may either be administered alone or in combination with another therapeutically active compound, wherein the two compounds may either be administered simultaneously or sequentially.
  • therapeutically active compounds which may advantageously be combined with compound I include sedatives or hypnotics, such as benzodiazepines; anticonvulsants, such as lamotrigine, valproic acid, topiramate, gabapentin, carbamazepine; mood stabilizers such as lithium; dopaminergic drugs, such as dopamine agonists and L-Dopa; drugs to treat ADHD, such as atomoxetine; psychostimulants, such as modafmil, ketamine, methylphenidate and amphetamine; other antidepressants, such as mirtazapine, mianserin and buproprion; hormones, such as T3, estrogen, DHEA and testosterone; atypical antipsychotics, such as olanzapine and aripiprazole; typical antipsychotics, such as haloperidol; drugs
  • the compounds of the present invention may be administered alone as a pure compound or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings.
  • Liquid dosage forms for oral administration include solutions, emulsions, drops, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants, etc.
  • the compounds of the invention are administered in a unit dosage form containing said compounds in an amount of about 0.1 to 50 mg, such as 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg 6, mg, 9 mg, 10 mg, 15 mg or 20 mg of a compound used in the present invention.
  • a unit dosage form containing said compounds in an amount of about 0.1 to 50 mg, such as 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg 6, mg, 9 mg, 10 mg, 15 mg or 20 mg of a compound used in the present invention.
  • typically doses are in the order of about half the dose employed for oral administration.
  • solutions of the compound of the invention in sterile aqueous solution aqueous propylene glycol, aqueous vitamin E, aqueous cyclodextrin, or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are microcrystalline cellulose, starch, gums, lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene, cyclodextrin and water.
  • compositions formed by combining the compound of the invention and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, drops, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be a tablet in powder or pellet form or in the form of a troche or lozenge. Alternatively, tablets, powders and pellets may be placed in a hard gelatine capsule. The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Adjuvants or additives usually used for purposes such as colouring, flavouring, preservation etc. may be used.
  • Capsules comprising a compound of the present invention may be prepared by mixing a powder comprising said compound with e.g. microcrystalline cellulose and magnesium stearate and place said powder in a hard gelatine capsule.
  • said capsule may be coloured by means of a suitable pigment.
  • capsules will comprise 0.1-10% of a compound of the present invention, such as 0.15-0.25%, 0.3-0.4%, 1.6- 1.8%, and 3.3-3.5% of a compound of the present invention - calculated as the free base. These strengths can be used to conveniently deliver 0.5, 1, 5 and 10 mg of a compound of the present invention in a unit dosage form.
  • Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials.
  • Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
  • the free base of compound I may be prepared as disclosed in WO 2005/061455.
  • Salts used in the present invention may be prepared by dissolving the free base in an appropriate solvent, adding the relevant acid, followed by precipitation. Precipitation may be accomplished either by the addition of a second solvent, and/or evaporation, and/or cooling.
  • the compounds may be synthesized as depicted below Step l
  • step 1 1 equivalent of 2,2-dithiobenzoic acid is mixed with 1.5-2.5 equivalent H 2 SO 4 , such as 2 equivalents, in methanol. The reaction is carried out at reflux temperature.
  • step 2 1 equivalent of 2,2-dithiobenzoic acid is mixed with 1.5-2.5 equivalent H 2 SO 4 , such as 2 equivalents, in methanol. The reaction is carried out at reflux temperature.
  • step 2 1 equivalent of the di-benzoic acid ester is suspended in DME under a protective atmosphere, such as N 2 , and cooled to 10-15 0 C upon which sulfurylchloride in DME in slight excess (1-1.3 equivalent) is added slowly while maintaining the temperature below 25°C.
  • a protective atmosphere such as N 2
  • 6-fluoro-indole around 2 equivalents
  • DME cooled to 10-15°c
  • the product from step 2 may be recovered be diluting the reaction mixture with EtOAc followed by a washing step with NaHCOs and NaCl.
  • the organic phase is concentrated and co-evaporated with toluene.
  • the product from step 2 is obtained as a precipitate.
  • step 3 to the ester dissolved in THF (1 equivalent) is added LiBH 4 slowly at around 2.5 equivalents. After addition, the temperature is raised to around 40 0 C. Around 2.5 equivalents of methanol is then added slowly while maintaining the temperature below 55°C. After completion of the reaction ( ⁇ 2 hours), citric acid (around 2.5 equivalents) is added to remove excess LiBH 4 . The organic phase is collected, concentrated and co-evaporated with iso- propanol. The mixture obtained is added slowly to water to allow precipitation, which precipitate is collected.
  • step 4 1 equivalent of the benzyl alcohol dissolved in THF is added to around 1.2 equivalent LiBr and around 1.5 equivalent NN-diisopropyl ethylamine (DIPEA). To this mixture, around 1.4 equivalent SO2CICH3 dissolved in THF is added while keeping the temperature below 50 0 C. The mixture is stirred for 15-20 hours to complete the reaction. To the mixture obtained, around 40 equivalents OfNH 2 CHs is added slowly, and the reaction is allowed to complete at around 40-45 0 C for approximately 5 hours. At this step, an appropriate acid may be added to afford the corresponding acid addition salt.
  • DIPEA NN-diisopropyl ethylamine
  • Dimethyl sulfoxide 99.8%D was used as solvent, and tetramethylsilane (TMS) was used as internal reference standard.
  • TMS tetramethylsilane
  • the melting points were measured using Differential Scanning Calorimetry (DSC).
  • the equipment was a TA-Instruments DSC-QlOOO calibrated at 5°/min to give the melting point as onset value. About 2 mg of sample was heated 5°/min in a loosely closed pan under nitrogen flow.
  • Thermo gravimetric analysis (TGA) used for estimation of solvent/water content of dried material was performed using a TA- instruments TGA-Q500. 1-10 mg sample was heated
  • test compound and rat cortical synaptosome preparation were pre-incubated for 10 min/37°C, and then added [ 3 H]NE or [ 3 H]5-HT (final concentration 10 nM).
  • Non-specific uptake was determined in the presence of lO ⁇ M talsupram or citalopram and the total uptake was determined in the presence of buffer.
  • Aliquots were incubated for 15 minutes at 37 0 C. After the incubation [ 3 H]NE or [ 3 H]5-HT taken up by synaptosomes was separated by filtration through Unifilter GF/C, presoaked in 0.1 % PEI for 30 minutes, using a Tomtec CellHarvester program. Filters were washed and counted in a Wallac MicroBeta counter.
  • Compound I is a potent inhibitors of both the serotonin reuptake and the noradrenalin reuptake with IC50 values of 0.4 nM and 4.4 nM, respectively, determined using compound concentrations covering three decades.
  • Compound I was tested for affinities towards the CC IA receptor and was found to exhibit an antagonistic profile with high affinity, K 1 14 nM.
  • membranes are thawed and homogenized in buffer using an ultra turrax and diluted to the desired concentration (5 ⁇ g/well ⁇ 5 ⁇ g/900 ⁇ l, store on ice until use).
  • the experiment is initiated by mixing of 50 ⁇ l test compound, 50 ⁇ l [ 3 H]-Prazosin and 900 ⁇ l membranes, and the mixture is incubated for 20 minutes at 25 0 C. Non-specific binding is determined in the presence of lO ⁇ M WB-4101 and the total binding is determined in the presence of buffer. After the incubation, bound ligand is separated from unbound by filtration through Unifilter GF/B, presoaked in 0.1 % PEI for 30 minutes, using a Tomtec Cell Harvester program (D4.2..4) 96 well. Filters are washed 3 times with 1 ml ice-cold buffer, dried at 50 0 C and 35 ⁇ l scintillation liquid/well is added to the filters.
  • Bound radioactivity is counted in a Wallac OY 1450 MicroBeta.
  • All cells were cultured in DMEM medium supplemented with 10% BCS, 4 mM L- glutamine (or 2 mM in the case of COS-7), and 100 units/ml penicillin plus 100 ⁇ g/ml streptomycin, at 37 oC, in 5% CO2.
  • CHO cells expressing the human alphal A- 7 receptors were seeded into 384-well black wall microtiter plates coated with poly-D-lysine.
  • Culture medium was aspirated and cells were dye-loaded with 1.5 ⁇ M Fluo-4 in assay buffer composed of Hank's Balanced Salt Solution (138 mM NaCl, 5 mM KCl, 1.3 mM CaCl 2 , 0.5 mM MgCl 2 , 0.4 mM MgSO 4 , 0.3 mM KH 2 PO 4 , 0.3 mM Na 2 HPO 4 , 5.6 mM glucose) plus 20 mM HEPES pH 7.4, 0.05% BSA and 2.5 mM probenicid (50 ⁇ l/well) for 1 hour in 5% CO 2 at 37 0 C.
  • Hank's Balanced Salt Solution 138 mM NaCl, 5 mM KCl, 1.3 mM CaCl 2 , 0.5 mM MgCl 2 ,
  • Rats were implanted with EEG and EMG electrodes to monitor the brain electrical activity and the muscle electrical activity, respectively.
  • the electrodes were connected to a radio transmitter allowing a continuous collection of activity data from freely moving, undisturbed and home-caged animals.
  • the EEG and EMG data were visually scored to determine the arousal states wake, SWS and REM sleep.
  • a group of 10 rats were administered vehicle or compound I corresponding to 0.4 mg/kg and 4 mg/kg of the free base.
  • a William's square cross over design was applied so that each animal receives each treatment once.
  • the table below shows the % of time spent in each arousal state during the second hour of recording, i.e. one to two hours post injection.
  • the table below shows the sleep latency in minutes, i.e. the time from injection of the compound until first consolidated sleeping episode.
  • cardiovascular effects of compounds of the present invention were investigated in telemeterised Beagle dogs in the doses 0.25, 0.50 and 1.0mg/kg given by gavage. Amount of compound is calculated as the free base. Six dogs were used in the experiment, three males and three females.
  • ABSP systolic arterial blood pressure
  • the group mean systolic left ventricular pressure was similarly reduced in all drug treated groups - see table below. A gender effect was seen for this parameter.
  • the alpha form of the L(+) hydrogen tartrate salt as prepared in example 6 or 7, is crystalline (XRPD) - see Figure 1.
  • the alpha form has a melting point of -193 0 C. It absorbs ⁇ 0.1% of water when exposed to high relative humidity and has a solubility of about 1.5 mg/ml in water, pH being 3.7 in the saturated solution.
  • Example 9 Preparation of the beta form of the L(+) hydrogen tartrate salt of [2-(6-Fluoro-lH-indol-3-ylsulfanyl)-benzyl]-methyl-amine (108,5g) was dissolved in methanol (1,7L) by warming on a hot water bath. L-(+)-tartaric acid (56,9g) was added, and the mixture stirred overnight at ambient temperature. The suspension was cooled on an ice bath for two hours. The solid was collected by filtration and washed with cold methanol. The product was dried in vacuum at 60 0 C. NMR complies with structure. Elemental analysis: 54.99%C, 6.25%N, 4.91%H (Theory for 1 :1 salt: 55.04%C, 6.42%N, 4.85%H).
  • Example 10 Characterisation of the beta form of the L(+) hydrogen tartrate salt
  • the beta form of the L(+) hydrogen tartrate salt, as prepared in example 9, is crystalline
  • the beta form has a melting point of ⁇ 189°C. It absorbs about 0.6% of water when exposed to high relative humidity and has a solubility of about 2.0 mg/ml in water, pH being 3.7 in the saturated solution.
  • Example 11 Antimanic effects - sensitised amphetamine response in mice
  • animals were maintained on a 12:12 light-dark cycle with lights on at 06:00 h. Food and water was available ad libitum. Animals were taken to the experimental laboratory in the afternoon the day before the experiment was conducted. All drug doses are listed as mg salt pr. kg. Blood-samples were collected within 30 minutes after the testing was finalised. Repeated intermittent administration of amphetamine causes development of a sensitised response to a subsequent amphetamine challenge. This phenomenon has been proposed to model the chronic and progressive nature of bipolar disorder.
  • mice Male NMRI mice weighing 19-2 Ig were supplied from Harlan, the Nederlands. The animals were housed 4 pr. cage in makrolon cages (20 x 35 cm) with two plastic houses and nesting material for enrichment. The animals had 5 days adaptation to the animal- facility prior to the initiation the experiment.
  • Makrolon cages (20 x 35 cm) placed in quadrates equipped with 5 x 8 infrared light sources and photocells spaced by 4 cm were used to record the locomotor activity of the animals.
  • the light beams cross the cage 1,8 cm above the bottom of the cage. Recording of a motility count required interruption of adjacent light beams, thus avoiding counts induced by stationary movements of the mice.
  • mice were pre-treated with either amphetamine sulphate 2,50 mg/kg (10 ml/kg s.c.) or vehicle for 5 consecutive days. After 11 +/- 1 days withdrawal period the animals were injected with test-drug or vehicle injection. Lithium chloride was dissolved in distilled water and injected s.c. (6 ml/kg) in dose of 40 mg/kg (0,94 mEq/kg), 30 minutes before testing.
  • Test compound [2-(6-fluoro-lH-indol-3-ylsulfanyl)benzyl]methyl amine L-(+)-hydrogen tatrate) was dissolved in 10 % hydroxypropyl-beta-cyclodextrin and injected s.c. in doses of 0,08 and 0,4 mg/kg 60 minutes before testing.
  • the tested doses of Test compound was combined with a dose of MDL 100907 ([R-(+)-a- (2,3- dimethoxyphenyl)-l-[2-(4-fluorophenylethyl)]-4-piperidinem ethanol]) that achieves full occupancy of this receptor. 30 minutes before testing the animals were placed in the activity boxes for habituation. After the habituation period the mice were injected with a low dose amphetamine challenge (1,25 mg/kg or saline, 10 ml/kg) and the locomotor activity were measured for 60 minutes. The mice were dosed after the average weight of 16 animals.
  • Increased locomotor activity induced by an appropriate combination of amphetamine and chlordiazepoxide is a proposed animal model of mania.
  • the induced locomotor activity can be reversed by Lithium.
  • mice Male Wistar rats weighing 160-175 g were supplied from Harlan, the Netherlands. The animals were housed 4 pr. cage in makrolon cages (20 x 35 cm) with one plastic house for enrichment. The rats had 5 days adaptation to the animal facility prior to the initiation of the experiment.
  • Makrolon cages (20 x 35 cm) placed in a U-frame equipped longitudinally with 4 infrared light sources and photocells were used to record the locomotor activity of the animals.
  • the light beams cross the cage 4 cm above the bottom of the cage. Recording of a motility count required interruption of adjacent light beams, thus avoiding counts induced by stationary movements of the rat.
  • a thin layer of standard bedding material coved the bottom of the cage.
  • Lithium Chloride was dissolved in distilled water and injected s. c. (6 ml/kg) in dose of 0,94 mEg/kg (40 mg/kg), 210 minutes before testing.
  • Test compound (see Example 12) was dissolved in 10 % hydroxypropyl-beta-cyclodextrin and injected s.c. in dose of 0,4 mg/kg alone or combined with 0,3 mg/kg MDL 100907 60 minutes before testing.
  • Amphetamine sulphate (1,2 mg/kg) was dissolved in 0,9 % NaCl and injected s.c. (1 ml/kg) 35 minutes before the test.
  • Chlordiazepoxide (10,0 mg/kg) was dissolved in 10 % hydroxypropyl- beta-cyclodextrin and injected s.c. (5 ml/kg) immediately after the amphetamine injection. 35 minutes after the amphetamine and chlordiazepoxide injections the animals was placed individually in test-boxes and the activity was measured for 120 minutes.
  • mice received vehicle or 0.625, 1.25, or 5 mg/kg (s.c.) Test compound (see example 12). 30 minutes after injection, animals were placed individually in cages containing 20 marbles (2 rows of 10) on top of 1.5 inches of Aspen bedding. After a 30-minute test period, mice were returned to their home cages, and the number of visible marbles (less than 2/3 covered with bedding) were counted and subtracted from 20 to give number of marbles buried.
  • the stress-induced hyperthermia (SIH) test is based upon the principle that, like other mammals, mice have a natural hyperthermic response to stress. In this paradigm, the stressor is having the rectal temperature taken. This physiological response is considered to reflect the anxiety level of the animal, and is attenuated by pretreatment with anxiolytic drugs such as benzodiazepines.
  • mice Male C57B1/6 mice (18-21 g) were housed 5/cage until 1 day before the experiment, at which time they were brought to the testing room and singly-housed. Testing was conducted over a two-day period from 9- 12am. Mice received vehicle, chlordiazepoxide (10mg/kg), or 0.02, 0.08, or 0.32 mg/kg Test compound (s.c). One hour later, core temperature was measured with a rectal probe (Tl) and each animal was returned to its cage. Ten minutes later, a second reading was obtained (T2). The difference between the two readings (T2 - Tl) was calculated as the measure of stress-induced hyperthermia.
  • Example 14 Crystalline salts of [2-(6-fluoro-lH-indol-3-ylsulfanyl)benzyl]methyl amine Dissolving 5 grams of [2-(6-fluoro-lH-indol-3-ylsulfanyl)benzyl]methyl amine in 100 ml EtOH produced a 0.175 M stock-solution in EtOH from which aliquots of 2.0 ml (100 mg of base) was used.

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Abstract

L’invention concerne une [2-(6-fluoro-1H-indol-3-ylsulfanyl)benzyl]méthyl amine et ses sels pharmaceutiquement acceptables pour le traitement des troubles du SNC.
PCT/EP2009/052899 2008-03-13 2009-03-12 [2-(6-fluoro-1h-indol-3-ylsulfanyl)benzyl]méthyl amine pour le traitement des troubles de l’humeur Ceased WO2009112541A2 (fr)

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