COMPOUND FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYSTEM DISORDERS

Abstract

The present invention relates to a pharmaceutical composition for use in the treatment and/or prevention of a central nervous system disorder, comprising a compound of formula (I):

##STR00001##

or any salt, derivative, isotope or mixture thereof, and at least one pharmaceutically acceptable excipient.

Claims

1.-23. (canceled)

24. A method of treating and/or preventing a central nervous system disorder in a subject in need thereof comprising a step of administration of a therapeutically effective amount of a pharmaceutical composition to said subject; wherein the pharmaceutical composition comprises a compound of formula (I) ##STR00007## or a pharmaceutically acceptable salt and/or solvate thereof, wherein: R.sub.1, R.sub.2 and R.sub.11 are each independently C.sub.1-C.sub.3 alkyl, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each independently selected from hydrogen, halogen, hydroxyl, —NH.sub.3, —NO.sub.3, —SH, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, and C.sub.1-C.sub.3 thioalkyl, and A is a 5- or 6-membered aromatic ring comprising 0, 1 or 2 nitrogen atoms, wherein the 5- or 6-membered aromatic ring is either not substituted or substituted by 1, 2, 3, or 4 groups, each group being independently selected from halogen, hydroxyl, —NH.sub.3, —NO.sub.3, —SH, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, and C.sub.1-C.sub.3 thioalkyl, and at least one pharmaceutically acceptable excipient.

25. The method according to claim 24, wherein A is selected from phenyl, pyridine, pyrrole, imidazole, pyrazole, diazine, and triazine.

26. The method according to claim 24, wherein the compound of formula (I) is a compound of formula (II) ##STR00008## or a pharmaceutically acceptable salt and/or solvate thereof, wherein: R.sub.1, R.sub.2 and R.sub.11 are each independently C.sub.1-C.sub.3 alkyl, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each independently selected from hydrogen, halogen, hydroxyl, —NH.sub.3, —NO.sub.3, —SH, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, and C.sub.1-C.sub.3 thioalkyl, and R.sub.12, R.sub.13, R.sub.15 and R.sub.16 are each independently selected from hydrogen, halogen, hydroxyl, —NH.sub.3, —NO.sub.3, —SH, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, and C.sub.1-C.sub.3 thioalkyl, and R.sub.14 is C.sub.1-C.sub.3 alkyl.

27. The method according to claim 24, wherein R.sub.1 is a methyl group, R.sub.2 is a methyl group, and/or R.sub.11 is an ethyl group.

28. The method according to claim 24, wherein: R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each independently selected from hydrogen and C.sub.1-C.sub.3 alkyl, R.sub.12, R.sub.13, R.sub.15 and R.sub.16 are each independently selected from hydrogen and C.sub.1-C.sub.3 alkyl, and R.sub.14 is C.sub.1-C.sub.3 alkyl.

29. The method according to claim 24, wherein the compound of formula (I) is compound (1) ##STR00009## or a pharmaceutically acceptable salt and/or solvate thereof.

30. The method according to claim 24, wherein the central nervous system disorder is selected from a motor disorder, a mood disorder, a neurological disorder, a neurodegenerative disorder, and an inflammatory disorder induced by a pathogenic factor or agent.

31. The method according to claim 30, wherein the motor disorder is selected from Parkinson's disease, Huntington disease, muscular disorders, multiple system atrophy, genetic and non-genetic dystonia including functional dystonia, restless legs syndrome, cerebellar disorders, and medication-induced motor disorder.

32. The method according to claim 30, wherein the motor disorder is Parkinson's disease.

33. The method according to claim 30, wherein the mood disorder is selected from psychotic disorders, schizophrenia, psychosis, bipolar disorder, bipolar depression, depression, anxiety, panic disorders, Tourette syndrome, obsessive compulsive disorders, and attention deficits disorders including attention deficit hyperactive disorders.

34. The method according to claim 30, wherein the mood disorder is anxiety.

35. The method according to claim 30, wherein the neurological disorder is selected from Epilepsy, Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI), Attention-Deficit Hyperactivity Disorder (ADHD), or Hyper-kinetic Disorder, agnosia, Amyotrophic Lateral Sclerosis (ALS), ataxia including Friedreich's ataxia, Canavan disease, dementia, neuralgia, migraine, headaches, and tension headaches.

36. The method according to claim 30, wherein the neurological disorder is epilepsy.

37. The method according to claim 30, wherein the neurodegenerative disorder is selected from Alzheimer's disease, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and Spinal muscular atrophy.

38. The method according to claim 30, wherein the neurodegenerative disorder is Alzheimer's disease.

39. The method according to claim 30, wherein the inflammatory disorder induced by a pathogenic factor or agent is selected from encephalitis, myelitis, meningitis, grey-matter atrophy, encephalopathy, HIV-induced neurological disorder, SARS-CoV-2-induced neurological disorder, neuronal destruction, infection or damage of oligodendrocytes, infection or damage of astrocytes, infection or damage of neurons, and apoptotic neurons.

40. The method according to claim 30, wherein the inflammatory disorder induced by a pathogenic factor or agent is selected from encephalitis, myelitis, meningitis, grey-matter atrophy, encephalopathy, HIV-induced neurological disorder, SARS-CoV-2-induced neurological disorder, and infection or damage of oligodendrocytes.

41. The method according to claim 24, wherein the method further comprises a step of administration of another therapeutic agent for the treatment and/or prevention of said central nervous system disorder.

42. The method according to claim 24, wherein the administration is oral administration.

43. The method according to claim 24, wherein the pharmaceutical composition is in the form of a film.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0157] FIG. 1 is a graph showing distance moved by zebra fish larvae treated with a vehicle (CTRL, open circles), pentetrazole at a concentration of 10 mM (black circles)

[0158] FIG. 2 is a graph showing distance moved by zebra fish larvae treated with pentetrazole at a concentration of 10 mM (black circles) or co-treated with pentetrazole at a concentration of 10 mM and Cmpd1 at a concentration of 100 μM (inverted white triangles) or with Cmpd1 at a concentration of 100 μM (open circles).

[0159] FIG. 3 is a graph showing distance moved by zebra fish larvae treated with a vehicle (CTRL, open circles), apomorphine at a concentration of 75 μM (black circles)

[0160] FIG. 4 is a graph showing distance moved by zebra fish larvae treated with apomorphine at a concentration of 75 μM (black circles) or co-treated with apomorphine at a concentration of 75 μM and Cmpd1 at a concentration of 100 μM (inverted white triangles).

[0161] FIG. 5 is a graph showing distance moved by zebra fish larvae treated with vehicle (CTRL, open circles) or Cmpd1 at a concentration of 100 μM (inverted black triangles).

[0162] FIG. 6 is a graph showing distance moved accumulated at 2 mM, 22 mM and 60 min by zebra fish larvae treated with a vehicle (CTRL, dotted line), pentetrazole at a concentration of 10 mM (solid line). The area of response to pentetrazole versus control is represented by connecting lines and pattern background. One-way anova with Tukey for multiple comparisons, CTRL vs PTZ ***P<0.001, **P<0.003.

[0163] FIG. 7 is a graph showing distance moved accumulated at 2 mM, 4 mM, 10 min, and 20 mM by zebra fish larvae treated with pentetrazole at a concentration of 10 mM (solid line) or co-treated with pentetrazole at a concentration of 10 mM and Cmpd1 at a concentration of 100 μM (dotted line) or with Cmpd1 at a concentration of 100 μM (dotted thin line). The areas of response to pentetrazole versus to treatment with Cmpd1 alone or in combination with pentetrazole are represented by connecting lines and pattern backgrounds. One-way anova with Tukey for multiple comparisons, Cmpd1+PTZ vs PTZ **P<0.002; Cmpd1 vs PTZ ***P<0.0001.

[0164] FIG. 8 is a graph showing distance moved accumulated at 2 min, 4 min, 10 min and 20 min by zebra fish larvae treated with a vehicle (CTRL, solid lines), apomorphine at a concentration of 55 μM (thin line). The area of response to apomorphine versus control is represented by connecting lines. One-way anova with Tukey for multiple comparisons, CTRL vs APO ***P<0.0003; **P<0.022.

[0165] FIG. 9 is a graph showing distance moved accumulated at 2 min, 22 min and 60 min by zebra fish larvae treated with apomorphine at a concentration of 55 μM (solid line) or co-treated with apomorphine at a concentration of 55 μM and Cmpd1 at a concentration of 65 μM (dotted line). The area of response to apomorphine versus to treatment with Cmpd1 in combination with apomorphine is represented by connecting lines and pattern background. One-way anova with Tukey for multiple comparisons, Cmpd1+APO vs APO **P<0.0046; Cmpd1 vs APO *P<0.06.

[0166] FIG. 10 is a graph showing distance moved accumulated at 2 min, 22 min and 60 min by zebra fish larvae treated with vehicle (CTRL, dotted line) or Cmpd1 at a concentration of 100 μM (solid line). The area of response to vehicle treatment versus to treatment with Cmpd1 is represented by connecting lines.

EXAMPLES

[0167] The present invention is further illustrated by the following examples.

Example 1: Cmpd1 in a Model of Epileptic Activity

[0168] Methods

[0169] Compound was tested in zebrafish paradigms reaction to environmental stimuli, epileptic activity and dopaminergic hyperactivity. Zebrafish used in present studies were raised in regular conditions of housing in tanks of appropriate size and circadian rhythm (12:12 photoperiod, light/darkness). The aqueous medium used for the maintenance and experimental conditions was Instant Ocean®. The water maintained between at 27° C. or 29° C., pH between 7.2-7.5 and a conductivity value between 480-520 μS. Zebrafish embryos were placed in sterile petri dishes before being transferred to plates after the hatching.

[0170] For experimental studies, larvae of up to 5 dpf were placed in flat bottom 96-well plates. At the treatment time, the medium was replaced by 150 μL fresh medium. Pentetrazole (PTZ) and/or Cmpd1 (treatment), or vehicle (control) were added (up to 210-240 μL) to the wells followed by video recording.

[0171] Locomotion of larvae was recorded using Noldus daniovisio system equipped with infrared light detection. Ethovision XT15 software controlled the temperature of plate (28° C.) and chamber light conditions. The experimental recording was done with a cycle of light period (20 min) followed by dark period (45 min). After recording data were analysed using Ethovision XT15 software package. The distance moved by larvae was calculated for each period of 2 min recording (FIGS. 1 to 6 and 10) or as accumulated value of distance at 2 min (initiation), at 4 min at 10 min and at 20 min (switch to darkness) or at 60 min (end of recording) (FIGS. 7 and 8).

[0172] All compounds were dissolved in medium or medium containing DMSO at indicated concentrations.

[0173] Results

[0174] Larvae treated with vehicle show a normal locomotor (FIGS. 1 and 5) with an increase of their activity after switch to dark condition, peaking after the minute 20 and decreasing afterwards till reach normal locomotion levels about the end of the recording.

[0175] Treatment of zebra fish larvae with pentetrazole, a pro-epileptic/seizure-inducing compound, induces a clear increase of locomotor activity in both light and dark conditions (FIGS. 1 and 2, black circles, and FIG. 6). This increase is associated to the seizure induced activity. Co-treatment with Cmpd1 at a concentration of 100 μM and pentetrazole at a concentration of 10 mM induced a decrease of the locomotor activity of ZF larvae induced by Pentetrazole alone (FIG. 2, inverted triangles, and FIG. 7). Cmpd1 stabilizes locomotion to levels close to normal locomotion observed in vehicle treated zebra fishes (FIG. 2, open circles, and FIG. 7).

[0176] These results thus show that Cmpd1 has an anti-epileptic activity.

Example 2: Cmpd1 in a Model of Hyperdopaminergic Activity

[0177] Methods

[0178] The same methods as disclosed in Example 1 ware carried out for Example 2, except that the pentetrazole was replaced by apomorphine (APO).

[0179] Results

[0180] Treatment of zebra fish larvae with apomorphine a dopamine agonist induces a clear increase of locomotor activity in light conditions (FIG. 3, black circles, and FIG. 8). This increase is associated to the hyperactivity of the dopaminergic neurotransmission pathways leading to motor hyperactivity.

[0181] Co-treatment with Cmpd1 at a concentration of 100 μM and apomorphine at a concentration of 75 μM (FIG. 4, inverted triangles), or 55 μM (FIG. 9) induced a decrease of the locomotor activity of zebra fish larvae induced by apomorphine alone.

[0182] Cmpd1 stabilizes locomotion to levels close to normal locomotion observed in vehicle treated zebra fish (FIG. 5, black inverted triangles, and FIGS. 9 and 10). Cmpd1 reduces apomorphine-induced locomotion activity strongly during the first period of the assay (up to ˜20 min, FIG. 9). Cmpd1 alone maintains a low level of locomotion activity suppressing also the peak due to change to dark condition (FIGS. 5 and 10).

[0183] Therefore, it has been demonstrated that Cmpd1 is a stabilizer of the hyperdopaminergic activity. Suppressive effect on the change light-to-dark indicates also an effect of Cmpd1 on the stress-mood disturbance induced by a challenging environment. These results suggest that the compound may be used to treat motor disorders and mood disorders.