Chromone derivative as a dopamine D3 receptor antagonist for its use for the treatment of autism spectrum disorder

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.

Claims

1. A method for inhibiting the appearance or progression of autism spectrum disorder or of one or more symptoms of autism spectrum disorder, comprising administering a 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 salt thereof, in a therapeutically effective amount to a patient in need thereof.

2. The method of claim 1, wherein the pharmaceutically acceptable salt is hydrochloride.

3. The method of claim 1, for inhibiting the appearance or progression of social interaction deficits.

4. The method of claim 2, for inhibiting the appearance or progression of social interaction deficits.

5. A method for inhibiting the appearance or progression of autism spectrum disorder or of one ore more symptoms of autism spectrum disorder, comprising administering a pharmaceutical composition comprising 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 salt thereof and a pharmaceutically acceptable excipient, in a therapeutically effective amount to a patient in need thereof.

6. The method of claim 5, wherein the pharmaceutically acceptable salt is hydrochloride.

7. The method of claim 5, for inhibiting the appearance or progression of social interaction deficits.

8. The method of claim 6, for inhibiting the appearance or progression of social interaction deficits.

9. The method of claim 5, wherein the pharmaceutical composition 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.

10. The method of claim 6, wherein the pharmaceutical composition 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.

11. The method of claim 7, wherein the pharmaceutical composition 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.

12. The method of claim 8, wherein the pharmaceutical composition 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.

Description

(1) FIG. 1 depicts the effects of acute administration of the compound of the invention on social interaction behavior of rats in the offspring of mothers treated with either saline or sodium valproate.

(2) Valproic acid or its valproate salts, are anticonvulsant 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 psychiatric mood disorder presenting with episodes of an elevated or agitated mood known as mania (or hypomania, depending on the severity) alternating with episodes of depression. Teratogenic effects (abnormalities linked to neural tube closure) of valproate have been known for 30 years from retrospective 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 91-103).

(3) In the ASD rat model, valproate is administered to pregnant females, at a determined embryonic day, typically the 12.sup.th day, which corresponds to the time of neural tube closure in this species, and the offspring, when observed during infancy and adolescence, present with marked and specific 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 incorporates 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.

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

(5) As used above, the term dopamine D3 receptor, D3 receptor or DRD3 denotes 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 denotes a compound that forms a complex with dopamine D3 receptor and acts as a combined agonist-antagonist, 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(?)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H(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 denotes a molecule 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.

(6) As used here, the term salts denotes inorganic acid, organic acid, inorganic base or organic base addition salts of the compound of the present 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 allergic 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 resorption 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.

(7) 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.

(8) According to the present 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 salt thereof, preferably hydrochloride, is used as a medicament for the treatment of ASD and notably the social interaction deficits.

(9) 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 salt thereof in a therapeutically effective amount to a patient requiring treatment.

(10) Moreover, the invention relates to pharmaceutical compositions containing 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 salt thereof, and a pharmaceutically acceptable excipient, for their use as medicament for the treatment of ASD, notably the social interaction deficits.

(11) As another embodiment, the invention relates to pharmaceutical compositions combining 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 salt thereof, with other medications that are known to be used to treat ASD patients, and a pharmaceutically acceptable excipient, for their use as medicaments for the treatment of autism spectrum disorder, notably the social interaction deficits.

(12) 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.

(13) The compositions according to the invention can be administered by the oral, transdermic, parenteral, 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-7-yl)-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 depends 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.

(14) The following examples illustrate the invention without limiting the scope thereof.

EXAMPLE 1

(15) 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 of the binding of [.sup.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.Math.liter.sup.?1. This same compound exhibits a noticeable affinity for dopamine D2 receptor that is 71 times weaker.

(16) 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

(17) 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 salt. 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).

(18) Method:

(19) Pregnant (embryonic day 8 max) female Sprague-Dawley rats [OFA (SD) Charles River Lyon, France] were quarantined for 4 days. Animals were group housed (2 per cage) in a full bottom cage (ML-H Cage, 370?235?180 mm, L?W?H; floor surface 870 cm.sup.2) in an environmentally controlled room (temperature 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 ?m pore diameter) freely available. Until weaning of offspring, animals were changed only once per week in order to disturb them as little as possible. Environmental enrichment (nesting material) was provided.

(20) 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.

(21) One sodium valproate- or saline-exposed rat and an unfamiliar na?ve rat were placed in opposite corners of an arena (black arena 70 cm?70 cm?30 cm, L?I?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 10 min.

(22) Results:

(23) The effects of acute administration of the compound according to the invention on social interaction behavior in the offspring of mothers treated with either saline or sodium valproate are summarized on FIG. 1.

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

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

(26) At 0.63 mg/kg the compound according to the invention significantly reduced the social interaction deficits induced by prenatal exposure to sodium valproate. At 2.5 mg/kg the compound according to the invention completely reversed these deficits.

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