New therapeutic uses of H3-ligands

Abstract

The present invention relates to a new therapeutic application involving low dose administration of a highly potent H3-ligand: (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide.

Description

[Technical field]

[0001] The present invention relates to new therapeutic applications involving the administration of low doses of highly potent histamine H3-receptor ligands. [Background technology]

[0002] WO2006 / 117609 discloses a compound of the formula:

[0003] [ka]

[0004] and uses thereof for treating and / or preventing CNS disorders, such as Alzheimer's disease; attention; wakefulness and memory disorders; cognitive deficits in psychopathology; disorders in the elderly; depressive or asthenic states; Parkinson's disease; obstructive sleep apnea; dementia with Lewy bodies; vascular dementia; dizziness; motion sickness; alcohol and other substance abuse; chronic pain; obesity; diabetes and the metabolic syndrome; sleep disorders; stress; psychotropic disorders; convulsions; depression; narcolepsy; disorders of the hypothalamic pituitary secretion, cerebral circulation and / or immune system; and / or for facilitating adaptation to night work or time shifts in healthy humans.

[0005] WO2006 / 117609 discloses that the ligands are widely suitable for administration to humans in unit doses typically comprised between 0.1 mg and 1000 mg administered once per day, preferably 1 to 500 mg administered once to four times per day, and even more preferably 10 mg to 300 mg administered twice per day. Similarly, pitolisant, another non-imidazole H3 antagonist approved for treating narcolepsy, is marketed in unit dosage forms (coated tablets) of 4.5 mg and 18 mg. The optimal approved therapeutic dose can be up to 36 mg daily. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2006 / 117609 [Non-patent literature]

[0007] [Non-Patent Document 1] Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000 [Non-Patent Document 2] Ashworth, S., et al., Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET. J Nucl Med, 2010. 51(7):1021~9 Summary of the Invention [Problem to be solved by the invention]

[0008] Generally speaking, it is desirable to identify drug candidates that are as potent as possible: greater efficacy generally comes with greater selectivity for the target, lower risk of off-target binding, and therefore greater clinical safety. It is therefore desirable to identify drug candidates that are as potent as possible and have the lowest possible effective dose. [Means for solving the problem]

[0009] Despite the disclosed doses of H3-ligands disclosed in WO2006 / 117609, the present inventors have now discovered that H3-ligands of the formula:

[0010] [ka]

[0011] It has been discovered that (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide (herein referred to as "compound (A)") unexpectedly exhibits an extremely favorable profile, thus allowing for substantially lower effective doses.

[0012] Therefore, in accordance with a first object, the present invention provides a compound of formula (A):

[0013] [ka]

[0014] and (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide or a pharma- ceutically acceptable salt thereof and / or a solvate of said compound (A) or a salt thereof, in human patients, is used to treat the following conditions: Alzheimer's disease; attention; wakefulness and memory disorders; cognitive disorders in psychopathology; cognitive, mood and vigilance disorders, especially in the elderly; depressive or asthenic states; Parkinson's disease; obstructive sleep apnea; dementia with Lewy bodies; vascular dementia; dizziness; motion sickness; obesity; diabetes and the metabolic syndrome; sleep disorders; stress; psychotropic disorders; epilepsy; depression; narcolepsy with or without cataplexy; substance abuse, especially alcohol dependence disorders, substance abuse disorders. for the treatment and / or prevention of disorders selected from: cognitive impairment in autism; chronic pain and chronic fatigue; fatigue, mood, vigilance and cognitive disorders after stroke; attention and vigilance disorders in ADHD (attention deficit hyperactivity disorder) in children or adults or after cerebrovascular accidents; disorders of the hypothalamic pituitary secretion, cerebral circulation and / or immune system; excessive daytime sleepiness, e.g. excessive daytime sleepiness and fatigue associated with Parkinson's disease, obstructive sleep apnoea or dementia; and / or for facilitating adaptation to night work or time shifts in healthy humans, said use comprising the administration of (A) to a human in a dose comprised between 10 and 90 μg per day (with respect to compound (A) in the form of the base).

[0015] Also disclosed herein is a method for the prevention and / or treatment of the above disorders, comprising administering to a patient in need thereof compound (A) in a dose comprised between 10 and 90 μg per day (with respect to compound (A) in the form of a base), together with a pharma- ceutically acceptable carrier or excipient.

[0016] According to one embodiment, the use is for treating and / or preventing sleep disorders, such as insomnia, sleep onset and sleep maintenance disorders, sleep fragmentation, parasomnia, REM sleep disorder, sleep breathing disorder, circadian rhythm disorder, narcolepsy with or without cataplexy, excessive daytime sleepiness (including "sleep attacks"), such as fatigue or excessive daytime sleepiness associated with Parkinson's disease, obstructive sleep apnea or dementia. Another use is for treating and / or preventing substance abuse disorders, especially alcoholism. Another use is for treating and / or preventing mood, cognition and vigilance disorders associated with stroke. Another use is for treating and / or preventing cognition and attention disorders in ADHD or after cerebrovascular accident.

[0017] According to one embodiment, compound (A) is in the form of its base as shown in formula (A). Alternatively, compound (A) may be in the form of a pharma- ceutically acceptable salt, such as hydrochloride, oxalate, dihydrochloride, hydrobromide, dihydrobromide, naphthalene-1,5-disulfonate, sulfate, ethane-1,2-disulfonate, cyclamate, toluenesulfonate, paratoluenesulfonate, thiocyanate, nitrate, methanesulfonate, dodecylsulfate, naphthalene-2-sulfonate, benzenesulfonate, dichloroacetate, glycerophosphate, 2-hydroxyethanesulfonate, aspartate, maleate, phosphate, ethanesulfonate, camphor-10-sulfonate, glutamate, alginate, pamoate, 2-oxo-glutarate, 1-hydroxy-2-naphthoate, malonate, gentisate, salicylate, tartrate, fumarate, galactarate, citrate, glucuronate, lactobionate, 4-aminosalicylate, glycolate, sesquiglycolate, glucoheptonate, pyroglutamate, mandelate, malate, hippurate, formate, gluconate, lactate, oleate, ascorbate, benzoate, succinate, 4-acetamidobenzoate, glutarate, cinnamate, adipate, sebacate, camphorate, acetate, caproate, nicotinate, isobutyrate, propionate, carate, laurate, palmitate, stearate, undecen-10-ate, caprylate, orotate, carbonate, 5-sulfosalicylate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate; and / or in the form of a solvate, e.g. hydrate, ethanolate, hemiethanolate. Thus, the expression "compound (A)" as used herein, unless otherwise specified, also refers to the pharma- ceutically acceptable salts and / or solvates of said compound of formula (A) or its salts, with the dihydrochloride salt being specifically mentioned.

[0018] The expression "Compound (A) in the form of a base" corresponds to compound (A) shown above.

[0019] According to one embodiment, compound (A) may be in the form of the following pharma- ceutically acceptable salts: (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrochloride tetrahydrate (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide oxalate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide L-tartrate and its trihydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide pamoate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide fumarate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide para-toluenesulfonate and its sestertihydrate (2.5) (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,5-naphthalenedisulfonate and its hemiethanolate monohydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide phosphate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide hydrobromide; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,2-ethanedisulfonate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sulfate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrobromide; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide orotate and its dihydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 5-sulfosalicylate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1-hydroxy-2-naphthoate and its monohydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 3-hydroxy-2-naphthoate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide (sesqui)glycolate and its monohydrate

[0020] According to one embodiment, the tetrahydrate form of the dihydrochloride salt of compound (A).

[0021] The tetrahydrate of Compound (A) is stable at a relative humidity in the range of at least 30% to 70%, which is an improved property compared to the hygroscopicity of the dihydrochloride salt already described, and is also stable at temperatures in the range of 20°C to 40°C.

[0022] The tetrahydrate of compound (A) exhibits one or more of the following characteristics: According to one embodiment, the tetrahydrate form of compound (A) exhibits a melting peak at around 191° C. as measured by capillary tube method. According to another embodiment, analysis by differential scanning calorimetry shows two endothermic events beginning at approximately 53° C. and 83° C., corresponding to the loss of four water molecules; the last event is observed beginning at approximately 191° C. According to another embodiment, the water content of the tetrahydrate of compound (A) is comprised between 14 and 16% by mass, typically about 15.3±0.7%.

[0023] According to one embodiment, the tetrahydrate form of compound (A) exhibits one or more of the X-ray powder diffraction lines set forth below:

[0024] [Table 1]

[0025] More specifically, it exhibits the following peaks:

[0026] [Table 2]

[0027] The tetrahydrate form of the dihydrochloride salt of Compound (A) has been shown to be very stable.

[0028] The tetrahydrate of the dihydrochloride salt of Compound (A) can be prepared by conventional methods such as solubilization from a solvent by concentration, addition of a non-solvent, and / or lowering the temperature.

[0029] According to one embodiment, the tetrahydrate of the dihydrochloride salt of compound (A) is: - dissolving the dihydrochloride salt of (A) in water; - concentrating until a solid is separated; and - drying the solids to a final moisture content of 15.3 ± 0.7% by mass The composition can be produced by a method comprising the steps of:

[0030] Alternatively, the tetrahydrate of the dihydrochloride salt of (A) can be prepared as follows: - Add aqueous hydrochloric acid to the base (A); - Add acetone; - Seed until solids separate; - Filter; and - Dry the solids to a final moisture content of 15.3 ± 0.7% by mass.

[0031] According to one embodiment, the daily dose of compound (A) for administration to humans is comprised between 20 and 50 μg per day (relating to compound (A) in the form of the base), preferably between 30 and 45 μg of base per day.

[0032] According to another embodiment, the method of the present invention may include administration of said doses of compound (A) at a frequency comprised between once every 3 days, once every other day (qod), once a day (qd).Preferably, administration may occur once a day.

[0033] It is to be understood that the dose of the present invention is the cumulative dose of each administered dose given within a single day.

[0034] Identification of those subjects in need of treatment for the diseases and conditions described herein is well within the ability and knowledge of one of ordinary skill in the art, and a clinician familiar with the art can readily identify those subjects in need of such treatment by using clinical tests, physical examinations, genetic tests, and medical / family history.

[0035] The actual dosage level of the compounds of formula (A) of the present invention can be varied to obtain an amount of the active ingredient effective to obtain the desired therapeutic response for a particular composition and method of administration. Thus, the selected dosage level will depend on the desired therapeutic effect, the route of administration, the duration of the desired treatment and other factors, such as the condition of the patient. The therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by using conventional techniques and observing results obtained under analogous circumstances. In determining a therapeutically effective amount, the attending diagnostician will take into account many factors, including, but not limited to: the species of the subject; its size, age, and general health; the specific disease involved; the extent of involvement or severity of the disease; the response of the individual subject; the particular compound administered; the mechanism of administration; the bioavailability of the administered formulation; the selected dosing regimen; the use of concomitant drugs; and other relevant circumstances. The amount of compound (A) required to achieve a desired biological effect will vary depending on many factors, including the dosage of the drug administered, the type of disease, the condition of the patient, and the route of administration. Generally speaking, the preferred dosage of the drug to be administered will likely depend on such variables as the type and extent of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, as well as the compound excipient formulation and its route of administration. The daily dose of Compound (A) will generally be less than 90 μg (based on the base) per patient per day.

[0036] According to further embodiments, the methods of the present invention also include administration of one or more additional active ingredients selected from anti-Parkinson's drugs such as levodopa, ropinorole, lisuride, bromocriptine, pramixepole, or from another class of anti-narcolepsy drugs or drugs purported to be anti-narcolepsy drugs, including modafinil.

[0037] Compound (A) can be formulated into a pharmaceutical composition by mixing with one or more pharma- ceutically acceptable excipients. The compositions can be conveniently administered in unit dosage form, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000, any of the methods well known in the pharmaceutical art. Compound (A) can be administered by various routes of administration, such as orally; parenterally, e.g., subcutaneously, intramuscularly, intravenously; sublingually, topically; locally; intratracheally; intranasally, transdermally, or rectally, and the active ingredient is combined in a pharmaceutical composition with a pharma- ceutically acceptable excipient or vehicle.

[0038] Therefore, according to another object, the present invention also relates to a pharmaceutical composition comprising compound (A) and a pharma- ceutically acceptable excipient or vehicle for use in treating and / or preventing the above-mentioned disorders, wherein compound (A) is administered in a dose comprised between 10 and 70 μg per day (relative to compound (A) in the base form). For topical application, the compositions of the present invention may be used as creams, gels, ointments or lotions. In particular, formulations suitable for parenteral administration include emulsions, suspensions, aqueous and non-aqueous injection solutions which are sterile and may contain suspending agents and thickening agents and antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient and have an appropriately adjusted pH.

[0039] According to the present invention, oral administration of the compound or composition in a suitable formulation is advantageously used. Formulations suitable for oral administration to a patient include discrete units such as capsules, tablets, etc., of soft or hard gelatin, each containing a predetermined amount of the compound of formula (A). Formulations also include powders; granules; solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions.

[0040] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to an animal, or human, as appropriate. As used herein, "a pharma- ceutically acceptable excipient, vehicle or carrier" includes, inter alia, diluents, adjuvants, excipients or vehicles. The use of such ingredients for pharma- ceutical active substances is well known in the art.

[0041] In the context of the present invention, the terms "treat" or "treatment" as used herein means to reverse, alleviate, inhibit or prevent the progression of the disorder or condition for which such term is used, or one or more symptoms of such disorder or condition.

[0042] "Therapeutically effective amount" means an amount of a compound / medicament according to the invention effective to produce a desired therapeutic effect.

[0043] In the present invention, the term "patient" or "patient in need thereof" contemplates a human or non-human mammal afflicted or likely to be afflicted by the above-mentioned disorders. Preferably, the patient is a human.

[0044] Compound (A) can be administered in unit dosage form, where the term "unit dose" means a single dose that can be administered to a patient and that remains a physically and chemically stable unit dose containing the active compound itself, or as a pharma- ceutically acceptable composition, and that can be easily handled and packaged. Suitable unit dosage forms include oral forms; sublingual, buccal, intratracheal, intraocular, intranasal forms, by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous, and rectal forms and implants.

[0045] A daily dose of between 10 and 90 μg according to the present invention can be achieved by administering half a unit dosage form, a single unit dosage form or two or more unit dosage forms according to the marketed unit dosage form, the daily dose to be administered and the frequency of administration as indicated by the practitioner.

[0046] Some salts of compound (A) are novel. According to another object, the present invention also relates to the following compounds per se: (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrochloride tetrahydrate (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide L-tartrate and its trihydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide pamoate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide fumarate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide para-toluenesulfonate and its sesquihydrate (2.5) (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,5-naphthalenedisulfonate and its hemiethanolate monohydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide phosphate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide hydrobromide; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,2-ethanedisulfonate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sulfate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrobromide; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide orotate and its dihydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 5-sulfosalicylate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1-hydroxy-2-naphthoate and its monohydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 3-hydroxy-2-naphthoate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide (sesqui)glycolate and its monohydrate DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] The following examples are included as illustrative, non-limiting embodiments of the present invention. EXAMPLES

[0048] Example 1 PK results in humans C of compound (A) given orally once daily at doses of either 60 or 90 μg max were reached approximately 2.5-3.5 h after dosing on days 1 and 10, averaging 121 and 171 pg / mL, and 172 and 344 pg / mL after a single dose and after repeated doses of 60 and 90 μg, respectively. The anti-insomnia activity of compound (A) at doses as low as 30 μg daily was evidenced by a delay in falling asleep when going to bed at night, whereas repeated treatment with 90 μg once daily for 10 days led to some insomnia. Mean t 1 / 2 was determined on the 10th day after multiple dosing and was approximately 33 h. Total body clearance (Clss / F) was reduced by 65% ​​and 74% after repeated dosing of 60 and 90 μg of Compound (A), respectively. Serum levels of Compound (A) after the 60 μg dose were 42% higher at C max and 73% higher AUC 0~24h As reflected in the % accumulation after repeated dosing (day 10) was higher than after a single dose (day 1). The % accumulation after repeated dosing was more pronounced at the 90 μg dose, and C max is 101% higher, and AUC 0~24h was 113% higher. Average C max and AUC 0~24h Based on dose-normalized ratios, Compound (A) serum exposure in human volunteers tended to increase greater than dose proportionally from od 60 to 90 μg on days 1-10. Steady state appears to be achieved after 7-8 days of treatment at the 60 μg dose.

[0049] Example 2 Determination of the active dose of compound (A) The therapeutic activity of a histamine H3-receptor antagonist / inverse agonist drug can be predicted by assessing the degree of occupancy of its target in the brain, namely the H3 receptor. The degree of occupancy by this agent can be reliably measured in humans by their displacement of the binding of selective radioactive probes labeled with short half-life radioisotopes such as 11C. Thus, PET imaging allows the non-invasive measurement of receptor occupancy. The imaging method requires the injection of a positron-emitting radiotracer that binds to the receptor and the subsequent measurement of this binding using a PET scanner. Radioligands selective for the H3 receptor have been developed, among which [ 11 C]GSK189254 is a high affinity histamine H3 receptor antagonist with good brain penetration and a terminal half-life of 1.6 + 0.4 hours. This tracer has recently been used to characterize the dose-response occupancy of novel histamine H3 antagonists, and [ 11 This provides validation of the ability of 11C-GSK189254 to measure H3 receptors using PET in humans (Ashworth, S., et al., Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET. J Nucl Med, 2010. 51(7):1021-9). This method allows predicting the therapeutic dose of new H3 receptor inverse agonists / antagonists in two steps: 1 / determine the degree of receptor occupancy associated with a dose that ensures a therapeutic effect of a known drug A and 2 / evaluate the dose of a new drug B that ensures the same receptor occupancy as the therapeutic dose of A. This strategy was applied by comparing H3R occupancy in healthy volunteers receiving the approved and marketed H3R inverse agonist pitolisant at its maximum oral therapeutic dose of 40 mg with occupancy by compound (A) given at several dosages. H3R occupancy after 40 mg of pitolisant in six healthy volunteers was found to be 82.33±8.71%. As shown below, very similar H3R occupancy was found at a dose of 60 μg of Compound (A), and at a dose of 30 μg of Compound (A), a very high degree of occupancy was still present after repeated treatment once daily for 10 days, especially when steady state was reached.

[0050] [Table 3]

[0051] Since dose-response studies of pitolisant show therapeutic activity in various pathologies (narcolepsy, Parkinson's disease or excessive daytime sleepiness associated with obstructive sleep apnea) at oral doses of 20-40 mg, the above results lead to the conclusion that the therapeutic dose of compound (A) is in the region of 30-60 μg. The latter compound is therefore deemed to be 1,000 times more potent than the marketed drug pitolisant.

[0052] Melting points are determined on a Buchi capillary melting point apparatus. Proton NMR spectra were recorded on a Varian 400 MHz NMR instrument. Chemical shifts δ are expressed in ppm. The following abbreviations are used to describe the signal patterns: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, ms=massif. The recorded spectra are consistent with the proposed structures.

[0053] Infrared spectra (range 4000-450 cm-1) were recorded on a THERMO Electron Corporation Nicolet 380 FT-IR equipped with an attenuated total reflection system. Wavelengths are in cm-1.

[0054] Example 3 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrochloride tetrahydrate Charge (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrochloride (210 g) and water (200 g) into an evaporation vessel. Set the temperature of the bath in the evaporation system to about 40° C. and stir the mixture until all precipitate has dissolved. Evaporate the water until the product separates as a solid form. The evaporation vessel containing the product is transferred to a vacuum tray dryer and the product is dried at 30° C. The product is transferred from the evaporation vessel to a practical drying vessel and drying is continued at 30° C. until the water content of the product is 15.3±0.5% by mass.

[0055] Example 4 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrochloride tetrahydrate Charge acetone (10 kg) and (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide (2.5 kg). Set the temperature to 30-40°C. Stir the mixture until the (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide is dissolved, filter through a pressure filter and concentrate. Add a solution of hydrochloric acid (32%, 1.84 kg, 2.1 equiv.) in water (2 kg). Set the temperature to 22-30°C and add acetone (6-7 L). After seeding, add acetone to a total volume of 20 kg at 22-30°C. Stir the suspension at 18-24°C for 1-2 hours and filter. Rinse the cake with a mixture of acetone (3.5 kg) and water (240 g). The product is dried in a vacuum tray dryer under nitrogen flow (Tmax=30° C.) until the water content is 15.0-16.5% by mass.

[0056] Example 5 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrochloride is treated with ethyl acetate, water, concentrated sodium hydroxide, and potassium carbonate to liberate the base. The phases are filtered through a pad of Celite and decanted. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base. The crude base is refluxed with diisopropyl ether and crystallized at room temperature. The resulting solid is filtered and dried under vacuum at 40° C. for 2 days to give pure (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base as a white solid that melts at 91° C. 1H NMR (DMSO-d6): 8.17 (d,2H), 7.69 (d,2H), 7.68 (d,2H), 7.00 (d,2H), 4.02 (t,2H), 2.72 (m,2H), 2.35 (t, 2H), 1.90-1.70 (ms,3H), 1.65-1.35 (ms,5H), 0.85-0.75 (ms,4H). IR (main bands): 2929, 2766, 1606, 1473, 1465, 1241, 1177, 1061, 1029, 822, 569, 515.

[0057] Example 6 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide oxalate (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base is dissolved in acetone and treated with a solution of 1 equivalent of oxalic acid in acetone. The resulting white suspension is stirred for 15 hours at room temperature, filtered, rinsed with acetone, and dried under vacuum at 40° C. for 2 days to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide oxalate as an off-white solid that melts at 102° C. 1H NMR (D2O): 8.12 (d,2H), 7.65 (d,2H), 7.58 (d,2H), 6.95 (d,2H), 4.06 (m,2H), 3.41 (m,1H), 3.34 (m,1H), 3.16 (m, 2H), 2.70 (t,1H), 2.43 (t,1H), 2.150 (m, 2H), 1.85-1.50 (ms,4H), 0.98 (m,1H), 0.79 (s,3H). IR (main bands): 2963, 2501, 1704, 1602, 1470, 1449, 1409, 1391, 1287, 1256, 1225, 1169, 1052, 826, 815, 766, 695, 574, 449.

[0058] Example 7 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide L-tartrate trihydrate (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base is dissolved in ethanol and treated with a solution of 1 equivalent of L-tartaric acid in ethanol. The resulting white suspension is sonicated, stirred at room temperature for 15 hours, filtered, rinsed with ethanol, and dried under vacuum at 45° C. for 15 hours to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide L-tartrate trihydrate as a white solid that melts at 86° C. 1H NMR (D2O): 8.19 (d,2H), 7.73 (d,2H), 7.66 (d,2H), 7.02 (d,2H), 4.40 (s,2H), 4.12 (m,2H), 3.46 (m,1H), 3.39 (m,1H), 3.21 (m, 2H), 2.75 (t,1H), 2.45 (t,1H), 2.15 (m, 2H), 1.89-1.61 (ms,4H), 1.05 (m,1H), 0.84 (s,3H). IR (Main Bands): 2982, 2882, 2500, 1650, 1600, 1470, 1260, 1213, 1114, 1070, 1046, 883, 674, 576, 477.

[0059] Example 8 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide pamoate (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base and 1 equivalent of pamoic acid are refluxed in ethanol. The resulting yellow suspension is stirred for 15 hours at room temperature and filtered. The solid (containing excess acid) is refluxed in ethanol, filtered while hot, and the filtrate is concentrated under reduced pressure and then dissolved in minimum hot ethanol. Methyl tert-butyl ether is added to induce precipitation of the salt. Stir for 2 days at room temperature, filter, rinse with methyl tert-butyl ether, and after filtration the solid is dried under vacuum at 45° C. for 15 hours to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide pamoic acid salt as a yellow solid that melts at 179° C. 1H NMR (DMSO-d6): 8.24 (s,2H), 8.17 (d,2H), 8.14 (d,2H), 7.71-7.65 (ms,6H), 7.18 (m,2H), 7.06-7.01 (ms,4H), 4.69 (s,2H), 4.09 (t,2H), 2.77 (t,1H), 2.14 (m, 2H), 1.85-1.61 (ms,4H), 1.07 (m,1H), 0.88 (s,3H). The invisible signals are hidden by the deuterated solvent peaks. IR (main bands): 2984, 2500, 1644, 1567, 1510, 1445, 1392, 1354, 1214, 1196, 810, 751, 596, 482, 401.

[0060] Example 9 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide fumarate (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base is dissolved in hot acetone and treated with a solution of 1 equivalent of fumaric acid in hot acetone. The resulting white gum is refluxed and then stirred at room temperature for 15 hours to give a white solid. After filtering, rinsing with acetone, and drying under vacuum at 45° C. for 15 hours, (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide fumarate is obtained as a white solid that melts at 135° C. 1H NMR (DMSO-d6): 8.18 (d,2H), 8.14 (d,2H), 7.70 (d,2H), 7.68 (d,2H), 7.01 (d,2H), 6.53 (s,2H), 4.04 (t,2H), 2.90 (m,2H), 2.56 (m, 2H), 2.06-1.85 (ms,3H), 1.75 (m,1H), 1.70-1.50 (ms,3H), 1.49 (m,1H), 0.88 (m,1H), 0.82 (s,3H). IR (Main Bands): 3161, 2500, 1713, 1656, 1574, 1470, 1403, 1339, 1257, 1235, 1144, 1110 1038, 983, 918, 840, 790, 756, 627, 573, 454.

[0061] Example 10 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide para-toluenesulfonate sesquihydrate (2.5) A suspension of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in water is treated with a solution of one equivalent of para-toluenesulfonic acid in water. The resulting homogeneous phase is lyophilized and allowed to outgas in open air at room temperature for 2 days to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide para-toluenesulfonate hemipentahydrate as an off-white solid that melts at 201° C. 1H NMR (D2O): 8.10 (d,2H), 7.62 (d,2H), 7.55 (d,2H), 7.49 (d,2H), 7.17 (d,2H), 6.92 (d,2H), 4.40 (s,2H), 4.03 (t,2H), 3.37 (m,1H), 3.30 (m,1H), 3.14 (m,2H), 2.71 (m,1H), 2.44 (m,1H), 2.20 (s,3H), 2.06 (m, 2H), 1.85-1.50 (ms,4H), 1.00 (m,1H), 0.79 (s,3H). IR (Main Bands): 2541, 2353, 1651, 1601, 1469, 1402, 1284, 1224, 1205, 1163, 1119, 1030, 1007, 943, 850, 820, 680, 628, 559, 521, 487.

[0062] Example 11 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,5-naphthalenedisulfonate monohydrate hemiethanolate A solution of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in ethanol is treated with a solution of 1 equivalent of 1,5-naphthalenedisulfonic acid in ethanol. The resulting suspension is stirred at room temperature for 15 hours, filtered, rinsed with ethanol, and dried under vacuum at 40° C. for 2 days to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,5-naphthalenedisulfonic acid salt monohydrate hemiethanolate as a white solid that melts at 276° C. 1H NMR (D2O): 8.65 (d,2H), 8.11 (d,2H), 8.00 (d,2H), 7.60 (d,2H), 7.53 (m,2H), 7.49 (m,2H), 6.86 (d,2H), 3.98 (t,2H), 3.37 (m,1H), 3.29 (m,1H), 3.09 (m,2H), 2.64 (t,1H), 2.36 (t,1H), 2.05 (m, 2H), 1.80-1.50 (ms,4H), 0.95 (m,1H), 0.77 (s,3H). IR (Main Bands): 3026, 1601, 1487, 1416, 1261, 1213, 1114, 1030, 983, 806, 764, 665, 609, 580, 526, 502.

[0063] Example 12 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide phosphate A suspension of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in water is treated with one equivalent of 85% phosphoric acid in water. The resulting homogeneous phase is lyophilized and allowed to outgas in open air at room temperature for 2 days to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide phosphate as a white solid that melts at 116°C. 1H NMR (D2O): 8.11 (d,2H), 7.64 (d,2H), 7.57 (d,2H), 6.95 (d,2H), 4.05 (m,2H), 3.42 (m,1H), 3.34 (m,1H), 3.15 (m, 2H), 2.70 (t,1H), 2.43 (t,1H), 2.10 (m, 2H), 1.85-1.50 (ms,4H), 0.99 (m,1H), 0.79 (s,3H). IR (main bands): 2975, 2883, 2398, 2351, 1603, 1470, 1259, 1216, 1046, 932, 871, 812, 524, 502, 485, 450.

[0064] (Example 13) (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide hydrobromide A solution of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in tetrahydrofuran is treated with one equivalent of 48% hydrobromic acid in water. The resulting suspension is stirred at room temperature for 15 hours, concentrated under reduced pressure, and azeotroped twice with ethanol to give a sticky solid. Dilution in hot acetonitrile, concentration under reduced pressure, and drying under vacuum at 40° C. for 2 days gives (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide hydrobromide as a white solid that melts at 76° C. 1H NMR (D2O): 8.15 (d,2H), 7.68 (d,2H), 7.62 (d,2H), 6.98 (d,2H), 4.09 (t,2H), 3.44 (m,1H), 3.36 (m,1H), 3.18 (m, 2H), 2.72 (m,1H), 2.45 (m,1H), 2.13 (m, 2H), 1.85-1.55 (ms,4H), 1.05 (m,1H), 0.82 (s,3H). IR (main bands): 3390, 2930, 2633, 2541, 2360, 1604, 1469, 1227, 1173, 1054, 1029, 945, 821, 568, 518, 487.

[0065] Example 14 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,2-ethanedisulfonate A suspension of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in water is treated with a solution of 1 equivalent of 1,2 ethanedisulfonic acid in water. The resulting homogeneous phase is lyophilized and allowed to outgas in open air at room temperature for 2 days to give a hygroscopic solid. Trituration in tetrahydrofuran, filtration and drying under vacuum at 40°C for 2 days gives (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,2-ethanedisulfonic acid salt as a beige solid that melts at 155°C. 1H NMR (D2O): 8.16 (d,2H), 7.69 (d,2H), 7.61 (d,2H), 6.98 (d,2H), 4.08 (t,2H), 3.44 (m,1H), 3.36 (m,1H), 3.18 (m, 2H), 2.72 (m,1H), 2.45 (t,1H), 2.12 (m, 2H), 1.85-1.55 (ms,4H), 1.02 (m,1H), 0.81 (s,3H). IR (main bands): 3390, 2944, 2726, 2355, 1600, 1472, 1218, 1166, 1131, 1022, 997, 823, 760, 544, 524, 500.

[0066] Example 15 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sulfate A suspension of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in water is treated with one equivalent of aqueous 5N sulfuric acid. The resulting homogeneous phase is lyophilized and allowed to outgas in open air at room temperature for 2 hours to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sulfate as an off-white solid that melts at 71° C. 1H NMR (D2O): 8.14 (d,2H), 7.67 (d,2H), 7.61 (d,2H), 6.97 (d,2H), 4.08 (t,2H), 3.42 (m,1H), 3.35 (m,1H), 3.18 (m, 2H), 2.73 (m,1H), 2.45 (m,1H), 2.12 (m, 2H), 1.85-1.55 (ms,4H), 1.03 (m,1H), 0.82 (s,3H). IR (main bands): 3377, 2931, 2357, 1604, 1470, 1285, 1229, 1174, 1027, 945, 821, 602, 568, 518, 487.

[0067] Example 16 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrobromide A solution of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in ethanol is treated with 2 equivalents of aqueous 48% hydrobromic acid in water. The resulting solution is precipitated with ethyl acetate and stirred at room temperature for 15 hours. After filtration, rinsing with ethyl acetate, and drying under vacuum at 40° C. for 15 hours, (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrobromide is obtained as an off-white solid that melts at 215° C. 1H NMR (D2O): 8.24 (d,2H), 7.76 (d,2H), 7.67 (d,2H), 7.03 (d,2H), 4.13 (t,2H), 3.49 (m,1H), 3.41 (m,1H), 3.25 (m, 2H), 2.78 (m,1H), 2.50 (t,1H), 2.18 (m, 2H), 1.90-1.60 (ms,4H), 1.08 (m,1H), 0.87 (s,3H). IR (Main Bands): 2930, 2632, 2352, 1601, 1471, 1410, 1292, 1261, 1210, 1182, 1050, 945, 823, 704, 678, 625, 569, 502, 485.

[0068] (Example 17) (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide orotate dihydrate A suspension of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in water is treated with a suspension of one equivalent of orotic acid in water. The resulting homogeneous phase is lyophilized and allowed to outgas in the open air at room temperature for 24 hours to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide orotate dihydrate as a white solid that melts at 125°C. 1H NMR (D2O): 8.14 (d,2H), 7.66 (d,2H), 7.59 (d,2H), 6.95 (d,2H), 5.98 (s,1H), 4.07 (t,2H), 3.43 (m,1H), 3.36 (m,1H), 3.18 (m, 2H), 2.72 (m,1H), 2.45 (m,1H), 2.11 (m, 2H), 1.85-1.55 (ms,4H), 1.04 (m,1H), 0.82 (s,3H). IR (main bands): 2957, 2789, 1667, 1633, 1605, 1472, 1409, 1355, 1285, 1226, 1176, 819, 765, 572, 539, 418.

[0069] (Example 18) (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 5-sulfosalicylate A solution of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in ethanol is treated with a solution of 1 equivalent of 5-sulfosalicylic acid dihydrate in ethanol. The resulting suspension is stirred at room temperature for 20 hours, filtered, rinsed with ethanol, and dried under vacuum at 45° C. for 24 hours to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 5-sulfosalicylic acid salt as a white solid that melts at 213° C. 1H NMR (D2O): 8.13 (d,2H), 8.06 (s,1H), 7.67 (d,1H), 7.63 (d,2H), 7.53 (d,2H), 6.90 (d,2H), 6.86 (d,2H), 4.04 (m,2H), 3.42 (m,1H), 3.34 (m,1H), 3.16 (m, 2H), 2.70 (m,1H), 2.43 (m,1H), 2.09 (m, 2H), 1.85-1.55 (ms,4H), 1.02 (m,1H), 0.81 (s,3H). IR (main bands): 2963, 2671, 2556, 2358, 1667, 1602, 1471, 1366, 1290, 1240, 1164, 1149, 1117, 1021, 878, 771, 667, 584, 503.

[0070] (Example 19) (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1-hydroxy-2-naphthoic acid salt monohydrate A solution of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in ethanol is treated with a solution of 1 equivalent of 1-hydroxy-2-naphthoic acid in ethanol and water. The resulting homogeneous phase is lyophilized and allowed to outgas in open air at room temperature for 24 hours to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1-hydroxy-2-naphthoic acid salt monohydrate as a beige solid that melts at 140°C. 1H NMR (DMSO-d6): 8.18 (d,2H), 8.15 (m,1H), 7.75-7.65 (ms,6H), 7.43 (m,1H), 7.35 (m,1H), 7.01 (d,2H), 6.97 (d,2H), 4.08 (t,2H), 3.10 (m,2H), 2.60 (m,1H), 2.10 (m, 2H), 1.85-1.60 (ms,4H), 1.02 (m,1H), 0.87 (s,3H). The invisible signals are hidden by the deuterated solvent peaks. IR (Main Bands): 3500, 2356, 1609, 1580, 1471, 1402, 1367, 1313, 1239, 1175, 1035, 984, 806, 774, 578, 491, 447, 426.

[0071] (Example 20) (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 3-hydroxy-2-naphthoate A solution of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in ethanol is treated with a solution of 1 equivalent of 3-hydroxy-2-naphthoic acid in ethanol. The resulting homogeneous phase is concentrated under reduced pressure to give an oily residue. Acetone is then added and the solution is concentrated under reduced pressure to give a yellow solid. A minimum of acetone and a drop of water are added and the resulting suspension is sonicated and stirred at room temperature for 20 hours. Filter, rinse with acetone and dry under vacuum at 45°C for 24 hours to give (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 3-hydroxy-2-naphthoic acid salt as an off-white solid that melts at 199°C. 1H NMR (DMSO-d6): 8.26 (s,1H), 8.18 (d,2H), 7.72 (d,1H), 7.70-7.65 (ms,4H), 7.56 (d,2H), 7.31 (t,1H), 7.13 (t,1H), 7.01 (d,2H), 6.94 (s,1H), 4.08 (t,2H), 3.11 (m,2H), 2.64 (m,1H), 2.11 (m, 2H), 1.85-1.60 (ms,4H), 1.02 (m,1H), 0.87 (s,3H). The invisible signals are hidden by the deuterated solvent peaks. IR (main bands): 2931, 2355, 1645, 1603, 1519, 1464, 1446, 1351, 1238, 1173, 841, 818, 739, 594, 577, 478.

[0072] Example 21 (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sesquiglycolate monohydrate A solution of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide base in tetrahydrofuran is treated with a solution of one equivalent of glycolic acid in tetrahydrofuran. The resulting suspension is stirred at room temperature for 24 hours. Filtering, rinsing with tetrahydrofuran, and drying under vacuum at 45°C for 24 hours gives (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sesquiglycolate monohydrate as an off-white solid that melts at 82°C. 1H NMR (D2O): 8.19 (d,2H), 7.71 (d,2H), 7.65 (d,2H), 7.01 (d,2H), 4.12 (t,2H), 3.48 (m,1H), 3.41 (m,1H), 3.22 (m, 2H), 2.76 (m,1H), 2.49 (t,1H), 2.17 (m, 2H), 1.90-1.60 (ms,4H), 1.06 (m,1H), 0.86 (s,3H). IR (main bands): 3258, 3102, 2930, 2356, 1603, 1470, 1411, 1287, 1232, 1177, 1059, 947, 819, 696, 568, 509, 456.

[0073] Example 22 Comparative pharmacokinetic data in mice Compounds were administered to male Swiss mice at doses approximating 1 mg base / kg. Plasma and brain samples were taken 24 hours later. Results, normalized to 1 mg base / kg, are shown in Table 1.

[0074] [Table 4]

[0075] To some extent, the exemplified compounds show similar absorption rates. The ratios of AUC of the examples to the AUC of the dihydrochloride tetrahydrate are shown in Table 2. The ratios all fit within the interval of 0.6 to 1.2, which is consistent with the similarity of experimental error associated with the tests.

[0076] [Table 5]

[0077] The striking results are for the pamoate salt (Example 8). Pamoate (embonic acid) salts are widely used to make sustained release drugs (see, for example, Zypadhera / Zyprexa relprevv, the pamoate salt of olanzapine given only every 2-4 weeks). Example 8 shows a similar AUC and similar time to Cmax compared to the dihydrochloride tetrahydrate (Example 4). Therefore, low doses of the claimed compound A are possible, regardless of its salts and / or solvates therefrom.

[0078] (Example 23) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide L-tartrate

[0079] [Table 6]

[0080] Example 24 XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide pamoate

[0081] [Table 7A]

[0082] [Table 7B]

[0083] (Example 25) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide fumarate

[0084] [Table 8A]

[0085] [Table 8B]

[0086] (Example 26) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide para-toluenesulfonate

[0087] [Table 9A]

[0088] [Table 9B]

[0089] Example 27 XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,5-naphthalenedisulfonate

[0090] [Table 10A]

[0091] [Table 10B]

[0092] (Example 28) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide phosphate

[0093] [Table 11]

[0094] (Example 29) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide hydrobromide Phase A

[0095] [Table 12]

[0096] (Example 30) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide hydrobromide Phase B

[0097] [Table 13A]

[0098] [Table 13B]

[0099] (Example 31) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,2-ethanedisulfonate

[0100] [Table 14A]

[0101] [Table 14B]

[0102] Example 32 XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sulfate Phase A

[0103] [Table 15]

[0104] (Example 33) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sulfate Phase B

[0105] [Table 16]

[0106] (Example 34) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide orotate

[0107] [Table 17]

[0108] Example 35 XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 5-sulfosalicylate

[0109] [Table 18]

[0110] (Example 36) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1-hydroxy-2-naphthoate

[0111] [Table 19A]

[0112] [Table 19B]

[0113] (Example 37) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 3-hydroxy-2-naphthoate Phase A

[0114] [Table 20]

[0115] (Example 38) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 3-hydroxy-2-naphthoate Phase B

[0116] [Table 21]

[0117] (Example 39) XRPD of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide glycolate

[0118] [Table 22]

Claims

1. For use in the treatment and / or prevention of disorders in human patients and / or in facilitating adaptation to night work or time shifts in healthy humans, a compound of formula (A): 【Chemistry 1】 or a pharma- ceutical composition comprising a 3S-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide or a pharma- ceutical acceptable salt thereof and / or a solvate of said compound (A) or a salt thereof, wherein said disorder is selected from the group consisting of Alzheimer's disease; attention; wakefulness and memory disorders; cognitive disorders in psychopathology; cognitive, mood and vigilance disorders; depressive or asthenic states; Parkinson's disease; obstructive sleep apnea; dementia with Lewy bodies; vascular dementia; dizziness; motion sickness; obesity; diabetes and the metabolic syndrome; sleep disorders; stress; psychotropic disorders; epilepsy; depression; nausea with or without cataplexy. leukocytosis; disorders of the hypothalamic pituitary secretion, of the cerebral circulation and / or of the immune system; excessive daytime sleepiness; substances; prevention of substance abuse withdrawal syndrome; attention deficit disorders; post-stroke fatigue, mood, cognitive and vigilance disorders; cognitive disorders in autism; chronic pain and chronic fatigue; attention and vigilance disorders of ADHD (Attention Deficit Hyperactivity Disorder) in children or adults or after cerebrovascular accidents, said use comprising the administration to a human of compound (A) or a pharma- ceutical acceptable salt thereof and / or said salt or solvate of compound (A) in a dose of base comprised between 10 and 90 μg per day (with respect to compound (A) in the form of the base).

2. 2. The pharmaceutical composition of claim 1, wherein the sleep disorders include insomnia, disorders of falling asleep and staying asleep, sleep fragmentation, parasomnias, REM sleep disorders, sleep-disordered breathing, circadian rhythm disorders, narcolepsy with or without cataplexy, excessive daytime sleepiness (including "sleep attacks").

3. Compound (A) is a hydrochloride, oxalate, dihydrochloride, hydrobromide, dihydrobromide, naphthalene-1,5-disulfonate, sulfate, ethane-1,2-disulfonate, cyclamate, toluenesulfonate, paratoluenesulfonate, thiocyanate, nitrate, methanesulfonate, dodecylsulfate, naphthalene-2-sulfonate, benzenesulfonate, dichloroacetate, glycerophosphate, 2-hydroxyethanesulfonate, aspartate, maleate, phosphate, ethanesulfonate, camphor-10-sulfonate, glutamate, alginate, pamoate, 2-oxo-glutarate, 1-hydroxy-2-naphthoate, malonate, gentisate, salicylate, tartrate, fumarate, galactarate, citrate, glucuronate, lactate, lactic acid salt ...

3. The pharmaceutical composition according to claim 1 or 2, in the form of a pharma- ceutically acceptable salt thereof selected from: tobionate, 4-aminosalicylate, glycolate, sesquiglycolate, glucoheptonate, pyroglutamate, mandelate, malate, hippurate, formate, gluconate, lactate, oleate, ascorbate, benzoate, succinate, 4-acetamidobenzoate, glutarate, cinnamate, adipate, sebacate, camphorate, acetate, caproate, nicotinate, isobutyrate, propionate, laurate, palmitate, stearate, undecen-10-ate, caprylate, orotate, carbonate, 5-sulfosalicylate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate; and / or solvates.

4. 4. The pharmaceutical composition according to claim 1, wherein compound (A) is in the form of a hydrochloride salt.

5. 5. The pharmaceutical composition according to claim 1, wherein compound (A) is in the form of a dihydrochloride salt.

6. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein compound (A) is in the form of the tetrahydrate of the dihydrochloride salt.

7. 7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the daily dose for administration to a human patient is comprised between 20 and 50 μg per day (relative to compound (A) in the base form).

8. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the daily dose for administration to a human is comprised between 30 and 45 μg per day (relative to compound (A) in the form of the base).

9. 9. The pharmaceutical composition according to any one of claims 1 to 8, wherein compound (A) is administered once a day or once every two days.

10. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein compound (A) is administered once a day.

11. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein compound (A) is administered via the oral route.

12. Compound (A) is (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrochloride tetrahydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide oxalate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide L-tartrate and its trihydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide pamoate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide fumarate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide para-toluenesulfonate and its 2.5 hydrate (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,5-naphthalenedisulfonate and its hemiethanolate monohydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide phosphate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide hydrobromide; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1,2-ethanedisulfonate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide sulfate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide dihydrobromide; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide orotate and its dihydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 5-sulfosalicylate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 1-hydroxy-2-naphthoate and its monohydrate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide 3-hydroxy-2-naphthoate; (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide (sesqui)glycolate and its monohydrate 12. The pharmaceutical composition according to any one of claims 1 to 11, selected from the group consisting of:

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