Combination, pharmaceutical composition and use of the combination

Abstract

The present invention relates to combinations of an H3 antagonist and an antidepressant, which exhibit synergistic wakefulness-promoting activity. (Pharmaceutical composition and use of the combination)

Description

1 / 14 “COMBINATION, PHARMACEUTICAL COMPOSITION AND USE OF THE COMBINATION”

[001] The present invention relates to innovative combinations and their uses for the treatment of wakefulness disorders in patients suffering from noradrenaline release deficiency.

[002] Wakefulness is controlled by several monoaminergic neuronal systems in the brain, primarily the histaminergic and noradrenergic systems, which are active during wakefulness and inactive during sleep. Increased release of histamine or noradrenaline therefore results in the promotion of wakefulness at the expense of sleep states.

[003] It is known that inverse agonists / antagonists of histamine H3 receptors (X. Ligneau et al, J. Pharmacol. Exp. Ther. 2007, 320, 365, JS Lin et al, Neurobiology of Disease 2008, 30, 74, RX Guo et al, Brit. J. Pharmacol. 2009, 157, 104) modulate sleep / wakefulness, increasing wakefulness.

[004] WO 2006 / 117609 describes H3 ligands, such as (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine oxide of the formula: (A) hereinafter referred to as “compound (A)”, its pharmaceutically acceptable salts, hydrates or hydrated salts.

[005] Pitolisante (Wakix®), that is, the monochloride salt of 1{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, was one of the first H3 inverse antagonists / agonists on the market and is currently authorized in Europe for the treatment of narcolepsy, with or without cataplexy.

[006] The effect of H3 antagonists on noradrenaline was Petition 870230067685, dated 02 / 08 / 2023, p. 12 / 33 2 / 14 described in AD Medhurst et al (J. Pharmacol. Exp. Ther. 2007, 321, 10321045), G. Flik et al (J. Mol. Neurosci. 2015, 56, 320-328) and JS Lin et al (Neurobiology of Disease 2008, 30,74-83).

[007] Antidepressants with noradrenaline reuptake inhibitor properties, such as duloxetine, reboxetine, atomoxetine, venlafaxine, etc. (C. Sanchez et al, Pharmacol. Biochem. Behav. 2007, 86, 468) increase wakefulness at the cost of deep sleep and / or REM sleep.

[008] Kallweit et al (Expert Opinion on Pharmacotherapy, vol. 18, no. 8, 2017, pp. 809-817) report on the pharmacological management of narcolepsy with depression and suggest, for example, venlafaxine.

[009] Lin et al (Neurobiology of Disease, vol. 30, no. 1, 2008, pp. 74-83) describe the use of tiprolysate combined with modafinil.

[0010] It has now been discovered that combining an H3 antagonist with an antidepressant selected from the noradrenaline reuptake inhibitors unexpectedly generates a huge increase in quiet wakefulness and a reduction in REM sleep, which are amplified / reduced, respectively, in a synergistic, supra-additive manner, compared to the effect of each compound administered alone.

[0011] According to the first object, the present invention therefore relates to a combination of: an antagonist or inverse agonist of H3 with the formula: R1 (I) where, in formula (I): R1 is H or methyl; Petition 870230067685, dated 02 / 08 / 2023, page 13 / 33 3 / 14 R2e Cl ou where * represents the attachment position to the phenyl ring; n is 0 or 1; and an antidepressant selected from the norepinephrine reuptake inhibitors.

[0012] According to one embodiment, the aforementioned H3 inverse antagonist / agonist is selected from one of the following compounds: and any of its pharmaceutically acceptable salts or solvates.

[0013] More specifically, the aforementioned H3 antagonist / inverse agonist is the hydrochloride salt of:

[0014] More specifically, the aforementioned antagonist / agonist reverse of dihydrochloride, tetrahydrate (hereinafter referred to as BP1.3656B).

[0015] According to one embodiment, the compounds can be found in the form of their free base or, alternatively, in the form of salts. Petition 870230067685, dated 02 / 08 / 2023, page 14 / 33 4 / 14 pharmaceutically aceitáveis, such as hydrochloride, oxalate, dihydrochloride, hydrobromide, dibromide, naphthalene-1,5-dyssulfonate, sulphate, ethane-1,2disulfonate, cyclamate, toluenosulfonate, paratoluenosulfonate, thiocyanate, nitrate, methanesulfonate, dodecylsulfate, naphthalene-2-sulfonate, benzenosulfonate, dichloroacetate, glycerophosphate, 2-hidroxyethanesulfonate, aspartate, maleate, phosphate, ethanesulfonate, camphor-10-sulfonate, glutamate, alginate, pamoate, 2-oxoglutarate, 1-hidroxy-2-naphthoate, malonate, gentisate, salicylate, tartrate, fumarate, galactarate, citrate, glucuronide, lactobionate, 4-aminoxacylate, glycolate, sesquiglycolate, glucoheptonate, pyroglutamate, mandelate, malate, hipurate, formate, gluconate, lactate, oleate, ascorbate, benzoate, succinate, 4-acetamidobenzoate, glutarate, cinamate, adipate, sebacate, camphorate, acetate, caproate, nicotinate, isobutyrate, propionate, caprate, caprylate, caproate, laurate, palmitate, stearate, undecen-10-oate,caprylate, orotate, carbonate, 5-sulfosalicylate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate and / or solvates, such as hydrates, ethanolate and hemiethanolate.,

[0016] Consequently, the term “compound”, as used herein, also designates its pharmaceutically acceptable salts and / or solvates, unless otherwise specified.

[0017] According to one embodiment, the antidepressant is selected from duloxetine, reboxetine, atomoxetine, desipramine, venlafaxine, and desvenlafaxine, more specifically duloxetine. According to another embodiment, the aforementioned antidepressant is not venlafaxine.

[0018] According to one embodiment, the aforementioned antidepressant is a noradrenaline reuptake inhibitor, selected from duloxetine, reboxetine, atomoxetine, desipramine and desvenlafaxine, particularly duloxetine, reboxetine, atomoxetine and desipramine.

[0019] According to an achievement: - the aforementioned H3 antagonist / inverse agonist is Petition 870230067685, dated 02 / 08 / 2023, page 15 / 33 5 / 14 selected from one of the following compounds: and any of its pharmaceutically acceptable salts or solvates; and The aforementioned norepinephrine reuptake inhibitor is selected from duloxetine, reboxetine, and atomoxetine.

[0020] According to one embodiment, the combination is the combination of N^ N O^^'^I^I ^^Cl, HCl (pitolyzing agent) with duloxetine.

[0021] According to another object, the present invention also relates to a pharmaceutical composition comprising a combination according to the present invention, wherein the two ingredients are administered simultaneously, separately or in stages over time.

[0022] According to another object, the present invention also relates to the combination according to the present invention for use in the treatment and / or prevention of selected disorders arising from excessive daytime sleepiness, substance abuse disorders such as alcohol and / or cognitive and attention deficit, in patients suffering from noradrenaline release deficiency.

[0023] Identifying these patients in need of treatment for the diseases and conditions described herein is well within the capabilities and knowledge of those skilled in the art. Physicians knowledgeable in the subject can easily identify them using clinical examinations, Petition 870230067685, dated 02 / 08 / 2023, page 16 / 33 6 / 14 physical exams, genetic testing, and medical / family history are required for patients needing this treatment.

[0024] According to one study, the aforementioned disorder is excessive daytime sleepiness and occurs in patients who suffer from: Narcolepsy with and without cataplexy. - Idiopathic hypersomnia; - daytime sleepiness disorders; Obstructive sleep apnea; - Circadian rhythm disorders of sleep and wakefulness; Parkinson's disease; or Prader-Willi syndrome.

[0025] According to an alternative interpretation, the aforementioned disorder is a deficit in cognition and attention and occurs in patients who suffer from attention deficit hyperactivity disorder (ADHD).

[0026] According to an alternative additional realization, the aforementioned disorder is excessive daytime sleepiness, cognitive and attention deficit, and occurs in patients suffering from depression.

[0027] According to yet another alternative interpretation, the aforementioned disorder is selected from substance abuse withdrawal syndromes.

[0028] It should be noted that the alternative realizations are not mutually exclusive and may be considered additionally to each other.

[0029] Actual dosage levels of compounds may vary in order to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a specific composition and method of administration. The dosage level selected therefore depends on the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors such as the patient's condition. Petition 870230067685, dated 02 / 08 / 2023, page 17 / 33 7 / 14

[0030] The attending diagnostic physician, as a subject matter expert, can readily determine the therapeutically effective amount using conventional methods and observing the results obtained under analogous circumstances. In determining the therapeutically effective amount, several factors are considered by the attending diagnostic physician, including, but not limited to: patient type; their size, age, and general health; the specific disease involved; the degree of involvement or severity of the disease; the individual patient's reaction; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosage regimen; the use of concomitant medication; and other relevant circumstances.

[0031] The amount of compounds needed to achieve the desired biological effect will vary depending on a number of factors, including the type of drug formulation to be administered, type of disease, patient's disease status, and route of administration.

[0032] In general terms, the preferred dosage of the drug to be administered will likely depend on variables such as the type and extent of progression of the disease or disorder, the general health status of the specific patient, the relative biological efficacy of the selected compound, the formulation of the compound's excipient, and its route of administration.

[0033] The daily dose of the H3(I) inverse antagonist / agonist can generally be between 1 pg and 50 mg per day per patient. As an illustration, the preferred doses of pitolisant are 5-40 mg / day, more preferably 10-30 mg / day and, for BP1.3656B, 1-100 pg / day, preferably 5-30 pg / day.

[0034] The daily dose of the antidepressant can generally be understood to be between 2 mg and 250 mg per day per patient. The doses illustrated are detailed below: Petition 870230067685, dated 02 / 08 / 2023, page 18 / 33 8 / 14 - Desipramine: 10-300 mg / day, preferably 25-200 mg / day; Duloxetine: 20-120 mg / day, preferably 30-60 mg / day; Venlafaxine: 35-375 mg / day, preferably 35-225 mg / day; Desvenlafaxine: 50-400 mg / day, preferably 50-100 mg / day; Atomoxetine: 10-100 mg / day, preferably 10-60 mg / day; Reboxetine: 2-12 mg / day, preferably 28 mg / day.

[0035] According to a further embodiment, the method according to the present invention also comprises the administration of one or more additional active ingredients, selected from anti-Parkinson drugs such as levodopa, ropinirole, lisuride, bromocriptine, pramixepol or selected from antinarcoleptic drugs or allegedly antinarcoleptic drugs of another class, including modafinil.

[0036] Compounds may be formulated into identical or distinct pharmaceutical compositions by mixing with one or more pharmaceutically acceptable excipients.

[0037] The compositions can be conveniently administered in unit dosage form and can be prepared by any of the methods well known in pharmaceutical art, as described, for example, in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000.

[0038] The compounds can be administered via various routes of administration, such as oral; parenteral, including subcutaneous, intramuscular and intravenous; sublingual, topical; local; intratracheal; intranasal; transdermal or rectal, wherein the active ingredients are combined with a pharmaceutically acceptable vehicle or excipient in one or two pharmaceutical compositions.

[0039] In particular, formulations suitable for parenteral administration are sterile and include emulsions, suspensions, Petition 870230067685, dated 02 / 08 / 2023, page 19 / 33 9 / 14 aqueous and non-aqueous injection solutions, which may contain suspending agents, thickening and antioxidant agents, buffers, bacteriostatics and solutes that make the formulation isotonic and have a pH appropriately adjusted to the desired patient blood. For topical application, the compositions according to the present invention may be used as creams, gels, ointments or lotions.

[0040] According to the present invention, oral administration of compound (I) or composition in an appropriate formulation is conveniently employed. Formulations that are appropriate for oral administration to patients include discrete units, such as capsules, such as soft or hard gelatin, and lozenges, each containing a predetermined amount of the compound of formula (I). They also include powder; granules; solutions or suspensions in aqueous or non-aqueous liquid; liquid oil-in-water emulsion or liquid water-in-oil emulsion. Formulations resistant to the gastrointestinal tract are also contemplated for oral formulations, particularly for duloxetine.

[0041] “Pharmaceutically acceptable” or “pharmaceutically acceptable” means molecular entities and compositions that do not produce an adverse, allergic or other adverse reaction when administered to animals or humans, as appropriate.

[0042] As used herein, “pharmaceutically acceptable vehicle, carrier or excipient” includes in particular diluents, adjuvants, excipients or vehicles. The use of these ingredients for pharmaceutical active substances is well known in the art.

[0043] In the context of the present invention, the term “treat” or “treatment”, as used herein, indicates reversal, relief, inhibition of progression or prevention of the disorder or condition to which the term applies, or one or more symptoms of that disorder or condition. Petition 870230067685, dated 02 / 08 / 2023, page 20 / 33 10 / 14

[0044] “Therapeutically effective quantity” indicates the quantity of compound / medicine according to the present invention, effective in producing the desired therapeutic effect.

[0045] According to the present invention, the term “patient” or “patient in need thereof” is intended to indicate a human or non-human mammal affected or prone to being affected by the above disorders. Preferably, the patient is a human being.

[0046] The compounds may be administered in unit dose forms, wherein the term “unit dose” indicates a single dose that is capable of being administered to patients and can be easily handled and packaged, remaining as a physically and chemically stable unit dose comprising the active compound itself, or as one or two pharmaceutically acceptable compositions.

[0047] The appropriate unit dosage forms comprise oral forms; sublingual, buccal, intratracheal, intraocular and intranasal forms, by inhalation, topical, transdermal, subcutaneous, intramuscular, intravenous and rectal forms and implants. Brief Description of the Figures

[0048] Figure 1 represents the drug-induced changes in the sleep-wake balance over 12 hours after dosing in rats (mean ± standard deviation of 15 to 16 individual values) in duration of quiet wakefulness (Figure 1A) and duration of REM sleep (Figure 1B) after administration of pitolisant and duloxetine.

[0049] Figure 2 represents the drug-induced changes in the sleep-wake balance over 12 hours after dosing in rats (mean ± standard deviation of 15 to 16 individual values) in duration of quiet wakefulness (Figure 2A) and duration of REM sleep (Figure 2B) after administration of compound BP1.3656B and duloxetine. Petition 870230067685, dated 02 / 08 / 2023, page 21 / 33 11 / 14

[0050] Figure 3 represents the drug-induced changes in the sleep-wake balance over 12 hours after dosing in rats (mean ± standard deviation of 15 to 16 individual values) in duration of quiet wakefulness (Figure 3A) and duration of REM sleep (Figure 3B) after administration of pitolisant and reboxetine.

[0051] Figure 4 represents the drug-induced changes in the sleep-wake balance over 12 hours after dosing in rats (mean ± standard deviation of 15 to 16 individual values) in duration of quiet wakefulness (Figure 4A) and duration of REM sleep (Figure 4B) after administration of pitolisant and atomoxetine.

[0052] Figure 5 represents the drug-induced increase in noradrenaline release in rat prefrontal cortex over baseline release (AUC over 150 minutes post-dosage) following administration of pitolisant and duloxetine (mean ± standard deviation of 6 to 9 individual values). Examples Example 1

[0053] Effect on sleep and wakefulness:

[0054] The effects on sleep and wakefulness parameters were investigated in male Wistar rats. Briefly, the rats received a stereotaxic implant with cortical electrodes for electroencephalogram (EEG) recording using a telemetry system (Data Sciences Int., Saint Paul MN, United States) to obtain, transfer, and store motor activity and EEG signals. The EEG signals were analyzed according to a procedure adapted from the algorithm proposed by RP Louis et al (J. Neurosci. Methods, 2004, 133, 71-80) and the analysis of wakefulness stages according to H. Kleinlogel (Neuropsychobiol. 1990-91, 23, 197-204) after fast Fourier transformation lasting eight seconds during EEG moments. This allows the determination, for each Petition 870230067685, dated 02 / 08 / 2023, page 22 / 33 12 / 14 moment, of their wakefulness stage (i.e., active wakefulness, quiet wakefulness, light or deep slow-wave sleep, and REM sleep, also called paradoxical sleep). Rats were orally given (by forced feeding) vehicle, drug, or drug combination approximately 30 minutes before the light onset. EEG signals were then continuously recorded and further integrated over the 12-hour daytime phase.

[0055] The effects on sleep and wakefulness recorded in rats of drugs alone or in combination are presented in Figure 1 (pitolysant / duloxetine), Figure 2 (BP1.3656B / duloxetine), Figure 3 (pitolysant / reboxetine) and Figure 4 (pitolysant / atomoxetine).

[0056] In the case of the combination of pitolisant and duloxetine, the combination was shown to generate a +35% increase in silent wave compared to the cumulative increase of +19%. Furthermore, when the two compounds are combined, the reduction in REM sleep offered by duloxetine is potentiated compared to the effect of duloxetine alone (-35% vs. -23%), while pitolisant alone for 12 hours has no significant effect. Example 2

[0057] Release of noradrenaline in the prefrontal cortex:

[0058] It is known that inverse agonists / antagonists of histamine H3 receptors (JS Lin et al, Neurobiology of Disease 2008, 30, 74, G. Flik et al, J. Mol. Neurosci. 2015, 56, 320) and noradrenaline reuptake inhibitors (FP Bymaster et al, Current Pharmaceutical Design, 2005, 11, 1475, FP Bymaster et al, Neuropsychopharmacol. 2002, 27, 699) increase extracellular noradrenaline in the prefrontal cortex and reflect the activation of noradrenergic neurotransmission. In both cases, however, the increase is limited.

[0059] The effects on noradrenaline release in the pre-cortical region Petition 870230067685, dated 02 / 08 / 2023, page 23 / 33 13 / 14 frontal lobes were investigated in vivo by microdialysis in awake male Wistar rats, as described by AD Medhurst et al (J. Pharmacol. Exp. Ther. 2007, 321, 1032-1045) and G. Flik et al (J. Mol. Neurosci. 2015, 56, 320-328). Briefly, anesthetized rats received implantation of guide cannulas for sampling in the prefrontal cortex. After at least one week of recovery following surgery, the microdialysis probe was inserted into the guide cannulas and underwent continuous perfusion with artificial cerebrospinal fluid (CSF). The rat was habituated to the microdialysis cage for approximately three hours. Rats then received orally (by forced feeding) vehicle, drug, or a combination of drugs. Samples of CSF collected every thirty minutes had their noradrenaline content analyzed using HPLC coupled with electrochemical detection.Sample levels of norepinephrine were expressed as a percentage of baseline norepinephrine release recorded over 1.5 hours prior to drug or vehicle treatment.

[0060] Unexpectedly, when the two types of compounds are combined, the activation of noradrenergic neurotransmission in the prefrontal cortex increases synergistically, as shown by the following data and illustrated in Figure 5. Maximum increase recorded over 150 minutes after dosing Drug Maximum increase (% of basic norepinephrine release) Statistical p-value vs. saline solution pitolisant duloxetine pitolisant +148±49% >0.05 duloxetine +113 ± 31% <0.05 combination +385 ±115% <0.05 <0.05 <0.05

[0061] In this way, combining the two classes of compounds can allow for a reduction in the dosage of each component and, therefore, an increase Petition 870230067685, dated 02 / 08 / 2023, page 24 / 33 14 / 14 of tolerance. Petition 870230067685, dated 02 / 08 / 2023, p. 25 / 33

Claims

1 / 3 Claims 1. COMBINATION, characterized by: an H3 antagonist or inverse agonist of formula: R1 (I) wherein, in formula (I): R1 is H or methyl; |^N'° R2 is Cl or , where * represents the phenyl ring attachment position; n is 0 or 1; and an antidepressant selected from noradrenaline reuptake inhibitors selected from duloxetine, reboxetine and atomoxetine.

2. COMBINATION, according to claim 1, characterized in that the aforementioned H3 antagonist / inverse agonist is selected from one of the following compounds: and any of its pharmaceutically acceptable salts or solvates. Petition 870230067685, dated 02 / 08 / 2023, page 26 / 33 2 / 3 3. COMBINATION, according to any one of claims 1 to 2, characterized in that the aforementioned H3 antagonist / inverse agonist is the hydrochloride salt of:

4. COMBINATION, according to any one of claims 1 to 3, characterized in that it is a combination of ^Cl or a pharmaceutically acceptable salt thereof with duloxetine.

5. COMBINATION, according to any one of claims 1 to 3, characterized in that it is a combination of, or a pharmaceutically acceptable salt thereof, with duloxetine.

6. COMBINATION, according to any one of claims 1 to 5, characterized in that the two ingredients are suitable for simultaneous, separate or staggered administration over time.

7. PHARMACEUTICAL COMPOSITION, characterized by comprising a combination, as defined in any one of claims 1 to 5, wherein the two ingredients are suitable for simultaneous administration.

8. USE OF THE COMBINATION, as defined in any of claims 1 to 5, characterized by being for the preparation of a Petition 870230067685, dated 02 / 08 / 2023, page 27 / 33 3 / 3 medication for the treatment and / or prevention of a selected disorder from excessive daytime sleepiness, substance abuse disorder such as alcohol and / or cognitive and attention deficit, in patients suffering from noradrenaline release deficiency.

9. USE, according to claim 8, characterized by the aforementioned disorder being excessive daytime sleepiness and occurring in patients suffering from: - narcolepsy with and without cataplexy; - idiopathic hypersomnia; - daytime sleepiness disorders; - obstructive sleep apnea; - circadian rhythm sleep-wake disorders; - Parkinson's disease; or - Prader-Willi syndrome.

10. USE, according to claim 8, characterized by the aforementioned disorder being a deficit in cognition and attention and occurring in patients suffering from attention deficit hyperactivity disorder (ADHD).

11. USE, according to claim 8, characterized by the aforementioned disorder being excessive daytime sleepiness, attention and cognitive deficit, and occurring in patients suffering from depression.

12. USE, according to claim 8, characterized by the aforementioned disorder being selected from substance abuse withdrawal syndromes. Petition 870230067685, dated 02 / 08 / 2023, pp. 28 / 33

Images