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• • A—HUMAN NECESSITIES
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Definitions

• the present invention relates to novel crystalline, water-soluble salts of the 2S,3S enantiomer of reboxetine, which are the fumarate and succinate salts thereof, to a process for their preparation, to their utility in therapy and to pharmaceutical compositions containing them.
• Reboxetine 2-[ ⁇ -(2-ethoxy-phenoxy)-benzyl]-morpholine, was first taught by GB 2014981B, which describes its utility for the treatment of depression.
• Reboxetine is a selective norepinephrine reuptake inhibitor, it is a safe drug and a superior treatment for those disorders in mammals, comprising humans, that need a selective norepinephrine reuptake inhibition. In fact it has few if any physiological effects besides those on norepinephrine processing, and therefore is free of side effects and unwanted activities.
• GB 2176407B provides single 2R,3R and 2S,3S enantiomers of reboxetine.
• the 2S,3S enantiomer of reboxetine hereafter named as SS-reboxetine, was found to be endowed with a selective norepinephrine reuptake inhibition activity significantly higher that racemate reboxetine.
• Reboxetine mesylate salt is on the market as racemate and is preferably administered in solid pharmaceutical forms.
• SS-reboxetine mesylate is under development for administration to mammals in solid pharmaceutical forms, which are the most appropriate for administration to patients in need of selective norepinephrine reuptake inhibition.
• compound SS-reboxetine mesylate has shown poor physicochemical characteristics and instability due to its hygroscopicity .
• Moisture uptake is a significant concern for pharmaceutical powders. Moisture have been shown to have a significant impact, for example, on the physical, chemical and manufacturing properties of drugs, excipients and formulations. It is also a key factor in taking decisions related to packaging, storage , handling and shelf life and successful development requires a sound understanding of hygroscopic properties. For instance, conversion from an anhydrous to a hydrate form may be observed when the relative humidity exceeds a critical level and moisture content rapidly increases in the solid. This has not only an impact on the physico-pharmaceutical properties of the drug per se, but also on its biopharmaceutical perspective.
• anhydrous mesylate salt is per se thermodynamically unstable and tends to transform itself with ageing into a hydrate form. Even more, the anhydrous form tends to lose its crystalline structure while exposed to high relative humidity environment, thus transforming it into a less chemically stable amorphous form.
• novel salts of SS-reboxetine having improved physico-chemical properties.
• the novel salts are crystalline, poorly hygroscopic, rapidly-dissolving solids with high water solubility and in addition are substantially more stable than the mesylate salt. They thus possess important advantages in handling, storage and formulations, etc., in addition to possessing all the other advantages, in particular therapeutic advantages, exhibited by the mesylate salt Description of the invention
• a first object the invention is to provide a novel crystalline, water-soluble salt of 2S,3S enantiomer of 2-[ -(2-ethoxy-phenoxy)-benzyl]-morpholine, which is the fumarate salt and the succinate salt thereof.
• Fumarate and succinate salts of SS-reboxetine can be obtained by known analogy methods by means of stoichiometric adding of aqueous solutions of the counterion to the free base dissolved in a suitable solvent.
• a suitable solvent is preferably an organic, in particular anhydrous, solvent chosen preferably from methanol, ethanol, dioxane and dimethylformamide.
• the precipitation of the obtained salt may be favoured by adding an anhydrous apolar solvent, for instance diethylether, n-hexane or cyclohexane.
• the free SS-reboxetine base can be obtained by the corresponding mesylate salt by known methods
• the mesylate salt of SS-reboxetine can be obtained as described in GB
• fumarate and succinate salts of SS- reboxetine can be obtained by reacting SS-reboxetine freebase with fumaric acid or succinic acid, respectively, in a suitable lower alkanol preferably ethanol, followed by controlled crystallization process.
• a lower alkanol is for instance a C1-C4 alkanol, preferably ethanol.
• SS-reboxetine freebase in its turn can be obtained by reacting SS-reboxetine mandelate with a suitable basic agent, for instance sodium hydroxide.
• SS-reboxetine mandelate in its turn can be obtained by reacting reboxetine freebase with (S)-(+)-mandelic acid in a suitable lower alkanol followed by controlled crystallization process.
• Reboxetine freebase can be obtained by reacting reboxetine mesylate with a suitable basic agent, for instance sodium hydroxide.
• the fumarate and succinate SS-reboxetine salts thus obtained have a crystalline structure.
• Object of the invention are also metabolites, metabolic precursors (also known as pro- drugs) and hydrate forms of SS-reboxetine fumarate and succinate salts.
• a further object of the invention is to provide a pharmaceutical composition
• a pharmaceutical composition comprising a salt of SS-reboxetine, which is the fumarate salt or the succinate salt thereof, as active ingredient and a pharmaceutically acceptable excipient and/or carrier.
• a pharmaceutical composition can be formulated according to known method in the art in any of the pharmaceutical forms known in the art for administration to a mammal, including humans.
• a pharmaceutical composition containing a compound of the invention, as an active ingredient, and a suitable carrier and/or excipient can be prepared as known from GB 201498 IB.
• a further object of the invention is to provide a salt of SS-reboxetine, which is the fumarate salt or the succinate salt thereof, for the use as a medicament, in particular as a selective norepinephrine reuptake inhibitor.
• a further object of the invention is to provide the use of a salt of SS-reboxetine, which is the fumarate salt or the succinate salt thereof, in the manufacture of a pharmaceutical composition for use in treating a mammal, comprising a human being, suffering from a disease state treatable by selective norepinephrine reuptake inhibition.
• a further object of the invention is to provide a method for treating a mammal, including a human being, in need of selective norepinephrine reuptake inhibition comprising administering to said mammal a therapeutically effective amount of a salt of SS-reboxetine, which is the fumarate salt or the succinate salt thereof.
• novel SS-reboxetine salts of the invention are useful for treating a mammal, comprising humans, suffering from a disease state treatable by selective norepinephrine reuptake inhibition.
• disease state treatable means that the treatment according to the invention provides remission of the disease state or, at least, the conditions and quality of life of the mammal under treatment are improved.
• diseases states are in particular nervous system disorders selected from the group consisting of addictive disorders (including those due to alcohol, nicotine, and other psychoactive substances) and withdrawal syndrome, adjustment disorders (including depressed mood, anxiety, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and mood), age-associated learning and mental disorders (including Alzheimer's disease), anorexia nervosa, apathy, attention- deficit (or other cognitive) disorders due to general medical conditions, attention-deficit hyperactivity disorder (ADHD), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, neuropathic pain, neuralgias including postherpatic neuralgias, conduct disorder, cyclothymic disorder, depression (including refractory depression, adolescent depression and minor depression), dysthymic disorder,
• addictive disorders including those
• novel SS-reboxetine salts of the invention can be used also in association with other therapeutic agents, for instance with pindolol for fast onset of antidepressant activity, with detrol for incontinence, and with a neuroleptic agent , e.g. a typical or atypical antipsychotic agent, to treat schizophrenia.
• a neuroleptic agent e.g. a typical or atypical antipsychotic agent
• the effective dose of SS-reboxetine fumarate or SS-reboxetine succinate salt may vary according to the disease, severity of the disorder and the conditions of the patient to be treated. Therefore the optimal dose for each patient, as always, must be set by the physician.
• the effective dosage range may be from about 0.5 mg/day to about 20 mg/day, preferably from about 1 to about 15 mg/day (calculated as free base), either as a single or multiple divided daily dosages.
• SS-reboxetine fumarate and SS-reboxetine succinate are readily orally absorbed, therefore they are preferably orally administered.
• they may be administered by any administration route, for instance by parenteral, topical, rectal and nasal route.
• Succinate salt of S,S-reboxetine has been synthesized by adding a stoichiometric amount of succinic acid to the ethanolic solution of the free base.
• Fumarate salt of S,S-reboxetine has been synthesized by means of the same stoichiometric crystallization technique described above.
• Step A Freebase reboxetine mesylate with aqueous sodium hydroxide into a dichloromethane phase. Evaporate dichloromethane from the reboxetine freebase and add ethanol. Dissolve 1.1 equivalents of (S)-(+)-mandelic acid in ethanol. Mix the freebase and acid solutions to form a precipitate of (S,S)-reboxetine mandelate following a controlled crystallization process. Isolate the solids by filtration and drying. Upgrade chiral purity of the (S,S)-reboxetine by reflux and recrystallization in ethanol. Isolate solids again by filtration and drying.
• Step B Freebase (S,S)-reboxetine mandelate with aqueous sodium hydroxide into a dichloromethane phase. Evaporate dichloromethane from the reboxetine freebase and add ethanol. Dissolve 1.0 equivalents of succinic acid in ethanol. Mix the freebase and acid solutions to form a precipitate of (S,S)-reboxetine succinate following a controlled crystallization process. Isolate the solids by filtration and drying.
• SS-reboxetine fumarate and SS-reboxetine succinate salts were characterized by X- ray powder diffraction (XRD), as follows:
• Powder X-ray diffraction was performed using a Siemens D-500 apparatus, irradiating powder samples with a CuK ⁇ graphite-monochromatic (40 kV 40 mA) source between
• succinate salt succinate salt
• fumarate salt succinate salt
• DSC analyses were carried out with a Perkin-Elmer DSC-7 apparatus. Aluminium DSC pans were loaded with about of 2 mg of sample. The temperature range of analysis was between 30° and 210°C. The samples were analyzed under nitrogen flow (to eliminate oxidative and pyrolitic effects) at a heating rate of 10°C/min.
• the water uptake of succinate and fumarate salts of S,S-reboxetine was investigated by submitting a sample of such salts to a hygroscopicity test by means of a DVS 1000 (SMS) according to the principle of Dynamic Moisture Sorption Gravimetry (DMSG).
• SMS Dynamic Moisture Sorption Gravimetry
• the apparatus is a "controlled atmosphere microbalance" where the weighed sample is exposed to programmed variations of the relative humidity (RH) at a constant and controlled temperature.
• RH relative humidity
• the measured parameters weight, time and RH
• the melting point determined by means of DSC analyses measuring the endothermic feature related to sample fusion, was about 106°C.
• the volatile content measured by means of Thermogravimetric Analysis was relevant: in fact, a weight loss of about 2% was detected upon heating showing a related thermal feature. Whereas for SS-reboxetine fumarate and succinate salts a negligible weight loss was measured.
• DSC profiles of SS-reboxetine succinate and fumarate salts were unchanged after equilibration at high humidity according to the DVS test method (maximum relative humidity of 90% at 25°C and equilibration up to 0.005%/min or no more than 360 minutes).
• mesylate salt was affected by a complete destructuration indicated by the disappearence of the main thermal feature (dehydration at about 50°C and melting at about 105°C).

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