OA17906A - A chromone derivative as a dopamine D3 receptor antagonist for its use for the treatment of autism spectrum disorder. - Google Patents

Abstract

The present invention claims a chromone derivative and pharmaceutical compositions and combinations comprising a least the said derivative, which is a dopamine D3 receptor antagonist, for their use for the treatment of autism spectrum disorder. Fig. 1

Description

Compound according to the invention (mg/kg)

Animais treated with saline

Animais treated with sodium valproate “ p<0.01 VS. Saline;

# p< 0,05 vs. Sodium valproate-exposed rats receiving saline;

## p< 0.01 vs. Sodium valproate-exposed rats receiving saline.

Ο.Α.Ρ.Ι. - B.P. 887, YAOUNDE (Cameroun) - Tel. (237) 222 20 57 00- Fax: (237) 222 20 57 27-Site web: http:/www.oapi.int - Email: oapi@oapi.int

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A CHROMONE DERIVATIVE AS A DOPAMINE D3 RECEPTOR

ANTAGONIST FOR ITS USE FOR THE TREATMENT OF AUTISM SPECTRUM DISORDER

The invention relates to the N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5g]chromen-7-yl)-butyl]-piperazin-1 -yl}-phenyl)-methanesulfonamide or a pharmaceutically acceptable sait thereof, for its use as médicament for the treatment of autism spectrum disorder.

Patent application WO 2011/027289 discloses chromone dérivatives, a process for their préparation and their therapeutic applications for the treatment of neurological or psychiatrie diseases. The chromone dérivatives according to WO 2011/027289 are dopamine D3 receptor partial agonists or antagonists.

Notably, WO 2011/027289 discloses the N-(3-{4-[4-(8-Oxo-8H- [1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)methanesulfonamide (Example N°21 of WO 2011/027289) corresponding to formula 1.

Among the diseases to be treated by the chromone dérivatives, WO 2011/027289 daims Parkinson's disease, psychosis, schizophrenia, dyskinesias associated with Parkinson's disease, cognitive deficiency optionally associated with âge or with Alzheimer's disease, mood disorder, essential tremor, anxiety, dépréssion, bipolar disorder, sexual impotence, prématuré éjaculation, alcoholism and nicotine addiction. Notably, WO2011/027289 does not disclose nor claim neurodevelopmental disorders.

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The neurodevelopmental disorders are a group of conditions with onset in the developmental period. These disorders typically manifest in childhood and are characterized by developmental déficits that produce impairment of Personal, social, academie, or occupational functioning. The range of disabilities varies from very spécifie limitations of learning or control of executive functions to global impairments of social skills or intelligence.

Among neurodevelopmental disorders, autism has been characterized as an infantile trouble distinct from psychoses and its signs and symptoms described by Kanner in 1943 (L. Kanner Autistic Disturbances of Affective Contact, Nervous Child 2:217-50, 1943), which includes various troubles in behaviour and skills. Autism included the typical infantile autism or Kanner’s autism, Asperger’s syndrome, which préserves language and cognitive functions and pervasive developmental disorder, not otherwise specified (commonly abbreviated as PDD-NOS), which was diagnosed when the full set of criteria for autism or Asperger syndrome were not met. Other classifications, like the International Statistical Classification of Diseases and Related Health Problems 10th Révision (ICD-10) from the World Health organization, includes even more subcategories. The variability of symptoms and présentations of autism among those various diagnostic categories made it difficult to comprehend to which particular symptom a therapeutic treatment was addressed.

Very recently however, the diagnosis of autism has markedly changed to recognize that social déficits distinguish autism and related disorders from other neurodevelopmental disorders (Rapin I, Tuchman RF. Autism: définition, neurobiology, screening, diagnosis. Pediatr Clin North Am. 2008;55(5):112946) and to unify the diagnosis under the unique name of Autism Spectrum Disorder (ASD). According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5, American Psychiatrie Association, American Psychiatrie Publishing, Washington D.C., 2013), ASD is characterized by persistent déficits in social communication and social interaction across multiple contexts, including déficits in social reciprocity, non verbal communicative behaviors used for social interaction, and skills in developing, maintaining and understanding

J relationships. In addition to the social communication déficits, the diagnosis of autism spectrum disorder requires the presence of restricted, répétitive patterns of behaviors, interests, or activities.

Within the diagnosis of ASD, individual clinical characteristics are noted through the use of specifiers that describe the autistic symptoms and their severity. Thus, according to DSM-5, the disorder is diagnosed with the following diagnostic criteria:

A: Social Communication and Interaction across multiple contexts (ail 3 required).

• déficits in social-emotional reciprocity.

• déficits in nonverbal communicative behaviors used for social interaction.

• déficits in developing and maintaining relationships.

B: Restricted, Répétitive Behavior (any 2 required).

• stereotyped or répétitive speech, motor movements, or use of objects.

• excessive adhérence to routines, ritualized patterns of verbal or nonverbal behaviors, or excessive résistance to change.

• highly restricted, fixated interests that are abnormal in intensity of focus.

• hyper-or hypo-reactivity to sensory input or unusual interest in sensory aspect of environment.

C: Symptoms must be présent in the early developmental period.

D: Symptoms cause clinically significant impairment of social, occupational, or other important areas of current functioning.

E: These disturbances are not better explained by intellectuel disability or global developmental delay.

ASD is a highly inherited neuropsychiatrie disorder: the concordance rate reaches up to 90% in monozygotic twins and 10% in dizygotic twins (reviewed in Won et al., Front. Mol. Neurosci. 2013, vol 6, art 19). However, ASD is an etiologically heterogeneous disorder in that no single genetic mutation accounts for more than 1-2% of cases (Abrahams et al., Nat. Rev. Genet. 2008, vol 9, p 341-355). Thus far, linkage and candidate-gene analyses, genome-wide association studies (GWAS), and assessments of chromosomal variations hâve uncovered a wide range of genes with predisposing mutations and polymorphisms associated with ASD (Persico et al., Behav. Brain Res. 2013, vol 251, p 95-112). None of these studies hâve identified the DRD3 as a susceptibility gene for ASD.

in 2009, de Krom and colleagues performed a genetic association study of 1,536 Single Nucléotide Polymorphisms (SNPs) présent in 132 candidate genes in a sample of 144 patients with ASD and 404 control individuals (de Krom et al., Biol. Psychiatr., 2009, vol 65, p 625-630). They found 31 single nucléotide polymorphisms positively associated at a P value lower than 0.01, which were tested in a second sample of 128 patients with ASD and 124 control individuals. Only the single nucléotide polymorphism rs167771 was found positively associated in the two ASD samples and in a joint statistical analysis. An association, which was not confirmed following statistical correction for multiple testing, was also found between the risk allele of rs167771 and a decreased risk of répétitive behaviour in patients with ASD, but not of other ASD symptomatic domains (Staal et al., J. Autism Dev. Disord. 2012, vol 42, p 885-888).

The single nucléotide polymorphism rs167771 is présent in the second intron ofthe dopamine D3 receptor gene. The dopamine D3 receptor is almost exclusively expressed in the central nervous System, particularly in the ventral striatal area, a brain région that plays an important rôle in the control of émotions and cognition (Sokoloff et al., Nature 1990, vol 347, p 146-151). The dopamine D3 receptor exists in two allelic forms generated by a single nucléotide polymorphism named rs6280 (also known as CM033372 or Bal\ polymorphism) in the coding sequence, which leads to two amino acid sequences containing either a serine (Ser) or a glycine (Gly) residue at the 9^th position (Lannfelt et al., Psychiatrie Genetics 1992, vol 2, p 249-256). The Gly/Gly allele is a gain-of-function allele, since it has a four times higher affinity for dopamine and is more responsive to dopamine than the Ser/Ser allele (Jeanneteau et al., Proc. Natl. Acad. Sci. USA 2006, vol 103, p 10753-10758). A therapeutic treatment based on intervention at the dopamine D3 receptor could be envisioned if the disorder to be treated is linked to either the gain-offunction (Gly/Gly allele) or loss-of-funotion (Ser/Ser allele). For instance, dopamine D3 receptor antagonists could be useful for treating a disorder linked to the Gly/Gly gain-of-function allele.

The elEnsembl genetic database of the human genome (available at http://www.ensembl.org) indicates that the two single nucléotide polymorphisms rs167771 and rs6280 belong to the same contig NT_005612.16 of the assembly GRCh37.p10 and are separated by 14,540 base-pairs. Data from linkage disequilibrium tables (also available at http://www.ensembl.org), indicate partial linkage disequilibrium between rs167771 and rs6280, with r square values (Pritchard et al., Am. J. Hum. Genet., 2001, vol 69, p 1-14) ranging from 0.245 to 0.610 in different populations. This indicates that the genetic association of rs167771 in ASD does not formally imply a linkage of ASD to the functional single nucléotide polymorphism rs6280 in dopamine D3 receptor. Accordingly, in another study on a small sample of 50 patients, rs6280 was not found to be associated with ASD (Martineau et al., Dev Med Child Neurol, 1994, 36:688697).

There is no cure for ASD. Atypical antipsychotics, such as rispéridone or aripiprazole, are approved by the US Food and Drugs Administration for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injury, temper tantrums and rapid mood changes, which do not belong to the core symptoms that define ASD. Adolescents and young adults with ASD are also prone to anxiety and dépréssion, which can be treated with antidepressant drugs such as sélective serotonin reuptake inhibitors. However, there is no approved treatment that targets the core symptoms ASD, i.e. déficits in social interactions and communication, and restricted interests.

Moreover, the genetic studies, are not conclusive and do not teach a method for treating ASD, especially the déficits in social interactions.

The inventors surprisingly found that the N-(3-{4-[4-(8-Oxo-8H- [1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)methanesulfonamide disclosed in WO 2011/027289 was of great benefit in an animal model that récapitulâtes core symptoms of ASD, which is based on prénatal exposure to valproate.

Valproic acid or its valproate salts, are anticonvulsivant drugs, e.g. Depakote®, used to treat epilepsy, a common and diverse set of chronic neurological disorders characterized by unprovoked seizures. Valproate is also used in the treatment of bipolar disorder, a psychiatrie mood disorder presenting with épisodes of an elevated or agitated mood known as mania (or hypomania, depending on the severity) alternating with épisodes of dépréssion. Tératogénie effects (abnormalities linked to neural tube closure) of valproate hâve been known for 30 years from rétrospective studies. Cases of ASD were also found in children from mothers who had taken valproate during their pregnancy, which led to warning on valproate and ASD risk in child-bearing women. Recently, the valproate-associated risk was confirmed by prospective studies, indicating that there is a 10-fold increase in the risk of ASD (Tomson et al., Lancet Neurol. 2012, vol 11, p 803-813; Bromley et al., J. Neurol. Neurosurg. Psychiatry 2013, vol 84, p 637-643). Valproate is supposed to cause ASD by interfering with epigenetic mechanism driving closure of the neural tube during intrauterine development (Kataoka et al., Int. J. Neuropsychopharmacol. 2013, vol 16, p 91103).

In the ASD rat model, valproate is administered to prégnant females, at a determined embryonic day, typically the 12^th day, which corresponds to the time of neural tube closure in this species, and the offspring, when observed during infancy and adolescence, présent with marked and spécifie behavioral abnormalities, accompanied by a few physical signs (reviewed in Roullet et al., Neurotoxicol. Teratol. 2013, vol 36, p 47-56). The valproate-induced behavioral abnormalities are strongly reminiscent of ASD symptoms and include:

• impairments of social behavior • stereotyped/repetitive patterns of behavior • sensory and communication impairment.

In addition, the phenotype also incorporâtes morphological rearrangements typical of ASD, such as reduced number or density of neuronal dendritic spines in the prefrontal cortex (Bringas et al., Neuroscience 2013, vol 241, p 170-187), which endows the valproate rat model with construct and face validities for a pathophysiological animal model of ASD.

In order to assess the potential of N-(3-{4-[4-(8-Oxo-8H-[1,3]dioxolo[4,5g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide hydrochloride, a potent dopamine D3 receptor antagonist (see Example 1) for treating ASD, the inventors hâve evaluated it in the ASD rat model (Example 2). As described in Example 2, the N-(3-{4-[4-(8-Oxo-8H-[1,3]dioxolo[4,5g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide hydrochloride was able to reverse social behavior déficit in prenatally valproateexposed young rats administered as a single dose. The inventors thus showed that the said compound can be used to treat ASD.

As used above, the term dopamine D3 receptor, D3 receptor or DRD3 dénotés a dopamine receptor sub-type chiefly expressed in the limbic System (Sokoloff P et al., Nature 1990, vol 347, p 146-151). Dopamine D3 receptor is described in international patent application WO 91/15513. As used above, the term D3 receptor partial agonist dénotés a compound that forms a complex with dopamine D3 receptor and acts as a combined agonistantagonist, that is to say it induces a physiological response of an intensity lower than that of the natural mediator, dopamine. In vitro, in a cell expressing dopamine D3 receptor, a dopamine D3 receptor partial agonist produces an active response the maximum intensity of which is lower than that produced by dopamine or by a full agonist, for example quinpirole (trans( - )-4aR4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1 H(or 2H)pyrazolo[3,4g]quinoline). A dopamine D3 receptor partial agonist may also partially prevent the response produced by dopamine or other full agonists. As used above, the term a dopamine D3 receptor antagonist dénotés a molécule that forms a complex with dopamine D3 receptor and is capable of preventing a response triggered by dopamine or an agonist thereof in a cell expressing dopamine D3 receptor.

As used here, the term salts dénotés inorganic acid, organic acid, inorganic base or organic base addition salts of the compound of the présent invention. As example, mention may be made of the salts derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric acids, and those derived from organic acids such as acetic, trifluoroacetic, propionic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic, stearic, lactic acids. Preferably, the salts are pharmaceutically acceptable, that is to say, they are non-toxic for the patient to whom they are administered. The expression pharmaceutically acceptable refers to molecular entities and compositions that do not produce any adverse allergie effect or other undesirable reaction when administered to an animal or human. When used herein, the expression pharmaceutically acceptable excipient includes any diluent, adjuvant or excipient, such as preservative, filler disintegrator, wetting agent, emulsifier, dispersant, antibacterial or antifungal agent, or also agents that would allow intestinal and digestive absorption and résorption to be delayed. The use of those media or vectors is well known in the art. Except where the agent is chemically incompatible with the compound according to the invention, its use in pharmaceutical compositions containing the compound according to the invention is envisaged.

In the context of the invention, the term treatment as used herein means preventing or inhibiting the appearance or progression of the condition to which the term is applied, or of one or more symptoms of that condition. Therapeutically active amount means an amount of a the compound according to the invention that is effective in obtaining the desired therapeutic effect according to the invention. According to the invention, the term patient refers to a human affected or very susceptible to being affected by ASD.

According to the présent invention, the compound (N-(3-{4-[4-(8-oxo-8H- [1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl) methanesulfonamide) or a pharmaceutically acceptable sait thereof, preferably hydrochloride, is used as a médicament for the treatment of ASD and notably the social interaction déficits.

The invention relates also to a treatment of ASD that comprises administering the compound (N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-

7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide) or a pharmaceutically acceptable sait thereof in a therapeutically effective amount to a patient requiring treatment.

Moreover, the invention relates to pharmaceutical compositions containing the compound (N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide) or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient, for their use as médicament for the treatment of ASD, notably the social interaction déficits.

As another embodiment, the invention relates to pharmaceutical compositions combining the compound (N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5g]chromen-7-yl)-butyl]-piperazin-1 -yl}-phenyl)-methanesulfonamide) or a pharmaceutically acceptable sait thereof, with other médications that are known to be used to treat ASD patients, and a pharmaceutically acceptable excipient, for their use as médicaments for the treatment of autism spectrum disorder, notably the social interaction déficits.

Preferably, the compound according to the invention is combined with a compound selected from the group consisting of memantine, amantadine, baclofen, R-baclofen, phenobam, acamprosate, bumetamide, carpipramine, oxytocin, vasopressin and mixtures thereof, and a pharmaceutically acceptable excipient.

The compositions according to the invention can be administered by the oral, transdermic, parentéral, nasal or rectal routes. The compositions can especially be administered by the oral route in an appropriate formulation. The dosages of the compound (N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide) in the compositions of the invention can be adjusted to obtain an amount of active substance that is effective in obtaining the desired therapeutic response for a composition peculiar to the method of administration. The dosage level chosen dépends therefore on the desired therapeutic effect, the administration route, the desired duration of treatment and other factors like patient body weight. The dosages can be from 0.001 to 10 mg per kg of body weight. The preferred dosages are in the range of 0.05 to 2 mg per kg of body weight.

The following examples illustrate the invention without limiting the scope thereof.

Example 1

The N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]piperazin-1-yl}-phenyl)-methanesulfonamide hydrochloride was evaluated in vitro as a dopamine D3 receptor ligand and modulator of the activity of that receptor in accordance with the invention in cells expressing human recombinant dopamine D3 receptor or human recombinant dopamine D2 receptor. The inhibition constant (Ki) was measured by inhibition ofthe binding of [³H] spiperone as described by Cussac et al., in Naunyn-Schmiedeberg's Arch. Pharmacol. 2000, vol 361, p 569-572. The inventors demonstrated that the compound according to the invention behaves as a potent dopamine D3 receptor ligand, with Ki values from 0.17 nanomole.liter¹. This same compound exhibits a noticeable affinity for dopamine D2 receptor that is 71 times weaker.

Compound according to the invention was evaluated for its agonist, partial agonist, or antagonist activity at dopamine D3 receptor by using the MAP-kinase activity test on human recombinant dopamine D3 receptor (Cussac et al., Mol. Pharmacol. 1999, vol 56, p 1025-1030). The intrinsic activity of this compound was null, indicating that it is a full antagonist.

Example 2

The N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]piperazin-1-yl}-phenyl)-methanesulfonamide hydrochloride was tested on social * ».

interaction of offspring of female rats which had been administered valproic acid as a sodium sait. The experimental settings of the valproic acid rat model of autism were adapted from published data (Dendrinos et al., Front. Integr. Neurosci. 2011, vol 5, art 68; Markram et al., Neuropsychopharm. 2007, vol 33, p 901-912; Schneider et al., Neuropsychopharm. 2005, vol 30, p 80-89).

Method:

Prégnant (embryonic day 8 max) female Sprague-Dawley rats [OFA (SD) Charles River Lyon, France] were quarantined for 4 days. Animais were group housed (2 per cage) in a full bottom cage (ML-H Cage, 370x235x180 mm, LxWxH; floor surface 870 cm²) in an environmentally controlled room (température 21 ± 1°C; relative humidity 55 ± 5%) under a 12-h light/dark cycle (lights on at 07:00 AM) with food (A04, Safe, Augy, France) and filtered water (0.2 pm pore diameter)freely available. Until weaning of offspring, animais were changed only once per week in order to disturb them as little as possible. Environmental enrichment (nesting material) was provided.

On embryonic days 12 and 13 (E12-E13), females were weighed and received three intraperitoneal injections of 2.4 ml/kg of sodium valproate (NaVPA, 200 mg/kg). Sodium valproate was dissolved in 0.9% saline for a concentration of 83.3 mg/ml, pH 7.3. Control dams received three intraperitoneal injections of saline (2.4 ml/kg). After the third injection, females were individually housed in ML-H type cages and allowed to raise their litters. Offspring were weaned between 21 to 23 days postnatally.

One sodium valproate- or saline-exposed rat and an unfamiliar naïve rat were placed in opposite corners of an arena (black arena 70 cm x 70 cm x 30 cm, L x I x H). Individual behavior related to social interaction such as following grooming, sniffing or biting the other rat as well as climbing over the other rat, initiated by the tested rat toward the unfamiliar rat were scored for a period of 10min.

Results:

The effects of acute administration of the compound according to the invention on social interaction behavior in the offspring of mothers treated with

G either saline or sodium valproate are summarized on Figure 1.

The data represented are the mean ± the standard error of the mean for n=10 rats (5females and 5 males).

The compound according to the invention had no significant effects on 5 social interaction behavior in the offspring of saline-treated mothers.

At 0.63 mg/kg the compound according to the invention significantly reduced the social interaction déficits induced by prénatal exposure to sodium valproate. At 2.5 mg/kg the compound according to the invention completely reversed these déficits.

The compound according to the invention is considered as an interesting product to treat autism spectrum disorders and more particularly the déficit of social interactions.

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Claims :

Claims (6)

1. Claims :

   1. The N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazin-1yl}-phenyl)-methanesulfonamide or a pharmaceutically acceptable sait thereof, for its use as médicament for the treatment of autism spectrum disorder.
2. 2. The N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazin-1yl}-phenyl)-methanesulfonamide for its use according to claim 1, wherein the pharmaceutically acceptable sait is hydrochloride.
3. 3. The N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazin-1yl}-phenyl)-methanesulfonamide for its use according to claim 1 or 2, for its use as médicament for the treatment ofthe social interaction déficits.
4. 4. A pharmaceutical composition comprising the N-(3-{4-[4-(8-oxo-8H- [1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)- methanesulfonamide or a pharmaceutically acceptable sait thereof and a pharmaceutically acceptable excipient, for its use for the treatment of autism spectrum disorder.
5. 5. A pharmaceutical composition for its use according to claim 4, for its use for the treatment ofthe social interaction déficits.
6. 6. A pharmaceutical composition for its use according to claim 4 or 5, combined with a compound selected from the group consisting of memantine, amantadine, baclofen, R-baclofen, phenobam, acamprosate, bumetamide, carpipramine, oxytocin, vasopressin and mixtures thereof.

   1/1

   250 η

   Compound according to the invention (mg/kg)

   Animais treated with saline Animais treated with sodium valproate ** p<0.01 vs. Saline;

   # p< 0.05 vs. Sodium valproate-exposed rats receiving saline;

   ## p< 0.01 vs. Sodium valproate-exposed rats receiving saline.

   Figure 1

   ABSTRACT

   The présent invention claims a chromone dérivative and pharmaceutical compositions and combinations comprising a least the said dérivative, which is a dopamine D3 receptor antagonist, for their use for the treatment of autism spectrum disorder.