NOVEL COMBINATIONS OF A H3 ANTAGONIST AND A NORADRENALINE REUPTAKE INHIBITOR, AND THE THERAPEUTICAL USES THEREOF

Abstract

Disclosed are combinations of a H3 antagonist and an antidepressant, which exhibit a synergistic wake promoting activity.

Claims

1. A combination of: a H3 antagonist or inverse agonist of formula: ##STR00009## Where in formula (I): R.sup.1 is H or Methyl, R.sup.2 is Cl or ##STR00010##  where * represents the position of attachment to the phenyl ring, n is 0 or 1, and an antidepressant chosen from the noradrenaline reuptake inhibitors.

2. The combination according to claim 1 wherein said antidepressant is not venlafaxine.

3. The combination according to claim 1 wherein said antidepressant is a noradrenaline reuptake inhibitor chosen from duloxetine, reboxetine, atomoxetine, desipramine, desvenlafaxine.

4. The combination according to claim 1, wherein said H3 antagonist/inverse agonist is chosen from one of the following compounds: ##STR00011## And any of their pharmaceutically acceptable salts, or solvates thereof.

5. The combination according to claim 1, wherein said H3 antagonist/inverse agonist is the hydrochloride salt of ##STR00012##

6. The combination according to claim 1, wherein said noradrenaline reuptake inhibitors are chosen from duloxetine, reboxetine, atomoxetine, desipramine.

7. The combination according to claim 1, wherein: said H3 antagonist/inverse agonist is chosen from one of the following compounds: ##STR00013## and any of their pharmaceutically acceptable salts, or solvates; and said noradrenaline reuptake inhibitor is chosen from duloxetine, reboxetine, and atomoxetine.

8. The combination according to claim 1 which is the combination of ##STR00014## or a pharmaceutically acceptable salt thereof, with duloxetine.

9. The combination according to claim 1 which is the combination of ##STR00015## or a pharmaceutically acceptable salt thereof, with duloxetine.

10. A pharmaceutical composition comprising a combination according to claim 1, wherein both ingredients are administered simultaneously, separately, or staggered over time.

11. A method for treating and/or preventing a disorder chosen from excessive daytime sleepiness, substance such as alcohol abuse disorders, and/or with attention and cognitive deficit, in a patient suffering from deficient noradrenaline release, comprising applying an effective amount of the combination of claim 1.

12. The method according to claim 11, wherein said disorder is excessive daytime sleepiness and occurs in a patient 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.

13. The method according to claim 11 wherein said disorder is attention and cognitive deficit and occurs in a patient suffering from attention deficit and hyperactivity disorder (ADHD).

14. The method according to claim 11 wherein said disorder is excessive daytime sleepiness, attention and cognitive deficit and occurs in a patient suffering from depression.

15. The method according to claim 11 wherein said disorder is chosen from substance abuse withdrawal syndromes.

16. The combination according to claim 2, wherein said antidepressant is a noradrenaline reuptake inhibitor chosen from duloxetine, reboxetine, atomoxetine, desipramine, desvenlafaxine.

17. The combination according to claim 2, wherein said H3 antagonist/inverse agonist is chosen from one of the following compounds: ##STR00016## And any of their pharmaceutically acceptable salts, or solvates thereof.

18. The combination according to claim 3, wherein said H3 antagonist/inverse agonist is chosen from one of the following compounds: ##STR00017## And any of their pharmaceutically acceptable salts, or solvates thereof.

19. The combination according to claim 2, wherein said H3 antagonist/inverse agonist is the hydrochloride salt of ##STR00018##

20. The combination according to claim 3, wherein said H3 antagonist/inverse agonist is the hydrochloride salt of ##STR00019##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] The invention will be described in connection with the attached drawings, in which:

[0066] FIG. 1 represents the drug-induced changes in sleep-wake balance over 12 hours post dosing in rats (Mean±SEM of 15 to 16 individual values) in quiet wake duration (FIG. 1A) and REM sleep duration (FIG. 1B) following administration of pitolisant and duloxetine.

[0067] FIG. 2 represents the drug-induced changes in sleep-wake balance over 12 hours post dosing in rats (Mean±SEM of 15 to 16 individual values) in quiet wake duration (FIG. 2A) and REM sleep duration (FIG. 2B) following administration of compound BP1.3656B and duloxetine.

[0068] FIG. 3 represents the drug-induced changes in sleep-wake balance over 12 hours post dosing in rats (Mean±SEM of 15 to 16 individual values) in quiet wake duration (FIG. 3A) and REM sleep duration (FIG. 3B) following administration of pitolisant and reboxetine.

[0069] FIG. 4 represents the drug-induced changes in sleep-wake balance over 12 hours post dosing in rats (Mean±SEM of 15 to 16 individual values) in quiet wake duration (FIG. 4A) and REM sleep duration (FIG. 4B) following administration of pitolisant and atomoxetine.

[0070] FIG. 5 represents the drug-induced increase in noradrenaline release in rat prefrontal cortex over basal release (AUC over 150 min post dosing) following administration of pitolisant and duloxetine (Mean±SEM of 6 to 9 individual values).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Examples

Example 1: Effect on Sleep/Wake

[0071] Effects on sleep/wake parameters were investigated in male Wistar rats. Briefly, rats were stereotaxically implanted with cortical electrodes for electroencephalogram (EEG) recording using a telemetric system (Data Sciences Int., Saint Paul, Minn., USA) for the acquisition, transfer and storage of motor activity and EEG signals. EEG signals were analysed according to a procedure adapted from the algorithm proposed by R. P. Louis et al. (J. Neurosci. Methods, 2004, 133, 71-80) and the analysis of vigilance stages according to H. Kleinlogel (Neuropsychobiol. 1990-91, 23, 197-204) after a fast Fourier transformation of 8-second duration EEG epochs. This allows the determination for each epoch of its vigilance stage (i.e. active wakefulness, quiet wakefulness, light or deep slow wave sleeps and REM sleep also named paradoxical sleep). Rats received orally (gavage) vehicle, drug or drug combination around 30 minutes before the light onset. Then, EEG signals were continuously recorded and further integrated over the 12-hour diurnal phase.

[0072] Effects on sleep/wake recorded in rats of drugs alone or combined are presented in the FIG. 1 (Pitolisant/duloxetine), FIG. 2 (BP1.3656B/duloxetine), FIG. 3 (pitolisant/reboxetine) and FIG. 4 (pitolisant/atomoxetine):

[0073] In the case of the pitolisant/duloxetine combination, the combination was shown to lead to an increase in the quite wake of +35% as compared to a cumulated increase of +19%. In addition, when the two compounds are combined, the decrease in the REM sleep elicited by duloxetine is potentiated compared to the effect of duloxetine alone (−35% vs. −23%) whereas pitolisant itself over 12 hours does not have any significant effect.

Example 2: Noradrenaline Release in the Prefrontal Cortex

[0074] Both histamine H3 receptor antagonist/inverse agonists (J. S. Lin et al. Neurobiology of Disease 2008, 30, 74, G. Flik et al. J. Mol. Neurosci. 2015, 56, 320) and noradrenaline reuptake inhibitors (F. P. Bymaster et al. Current Pharmaceutical Design, 2005, 11, 1475, F. P. Bymaster et al. Neuropsychopharmacol. 2002, 27, 699) are known to enhance the extracellular noradrenaline in the prefrontal cortex and reflecting an activation of the noradrenergic neurotransmission. However, in both cases, the enhancement is limited.

[0075] Effects on noradrenaline release in the prefrontal cortex were investigated in vivo by microdialysis in vigil 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, anaesthetized rats were implanted with a guide cannulae for sampling in the prefrontal cortex. After at least one week of recovery post-surgery, the microdialysis probe was inserted in the guide cannulae and perfused continuously with artificial cerebrospinal fluid (CSF). The rat was habituated to the microdialysis cage for ˜3 hours. Then, rats received orally (gavage) vehicle, drug or drug combination. CSF samples collected every 30 minutes were analysed for their noradrenaline content by HPLC coupled to a electrochemical detection. Noradrenaline sample levels were expressed in percentage of basal noradrenaline release recorded over 1.5 hour before vehicle or drug treatment.

[0076] Unexpectedly, when the two types of compounds are combined, the activation of the noradrenergic neurotransmission in the prefrontal cortex is enhanced in a synergistic manner as shown by the following data and illustrated in FIG. 5:

TABLE-US-00001 Maximal increase recorded over 150 min post dosing Maximal increase (% of basal statistics p value versus drug noradrenaline release) saline pitolisant duloxetine pitolisant +148 ± 49%  >0.05 duloxetine +113 ± 31%  <0.05 combination +385 ± 115% <0.05 <0.05 <0.05

[0077] Hence, the association of the two classes of compounds may allow a decrease in the dosage of each component and, thereby, enhanced tolerance.