WO2012020270A1

WO2012020270A1 - Use of radiprodil in attention deficit hyperactivity disorder

Info

Publication number: WO2012020270A1
Application number: PCT/HU2011/000082
Authority: WO
Inventors: Károly TIHANYI; Krisztina GÁL; Klára FELSZEGHY; Csaba Nyakas
Original assignee: Richter Gedeon Nyrt
Current assignee: Richter Gedeon Nyrt
Priority date: 2010-08-11
Filing date: 2011-08-10
Publication date: 2012-02-16
Anticipated expiration: 2013-02-11
Also published as: HUP1000424A2; HU1000424D0

Abstract

Radiprodil (chemical name: 2-[4-(4-fluoro-benzyl)-piperidine-l-yl]-2-oxo-N-(2-oxo-2,3- dihydro-benzoxazole-6-yl)-acetamide) and its pharmaceutically acceptable salt or hydrate, a NMDA receptor antagonist, is used to treat attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD).

Description

A

Use of radiprodil in attention deficit hyperactivity disorder Field of the invention The present invention relates to a new pharmaceutical uses of radiprodil (chemical name: 2- [4-(4-fluoro-benzyl)-piperidine-l-yl]-2-oxo-N-(2-oxo-2,3-dihydro-benzoxazole-6-yl)- acetamide), its hydrates and its pharmaceutically acceptable salt in the treatment of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive- compulsive disorders (OCD).

Background of the invention

Attention deficit hyperactivity disorder (ADHD) is a disorder of childhood that sometimes continues into adulthood. ADHD can be characterized by symptoms such as inattention, impulsivity and hyperactivity.

Methylphenidate has been used to treat such patients and it often significantly improves their ability to function and coexist with other people. Imipramine, desipramine, nortriptyline, amitriptyline, atomoxetin and clomipramine are also used in some cases of attention- deficit/hyperactivity disorder (ADHD).

These drugs labeled for use in ADHD are directed at modulating CNS catecholamine levels. They belong to the stimulant drug class which are considered drugs with abuse potential and as such are classified as controlled substances. Thus, the development of additional safe and effective, non-stimulant pharmacologic options would be of great clinical benefit to the ADHD population.

WO 03/010159 discloses radiprodil (chemical name: 2-[4-(4-fluoro-benzyl)-piperidine-l-yl]- 2-oxo-N-(2-oxo-2,3-dihydro-benzoxazole-6-yl)-acetamide) as NR2B (NMDA) receptor antagonist piperidine derivative and its use as pharmaceuticals, especially in the treatment of CNS disorders. Summary of the invention

It has surprisingly found that radiprodil and its pharmaceutically acceptable salt or hydrate are highly effective in the treatment, delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD).

The present invention relates to pharmaceutical composition comprising radiprodil or its pharmaceutically acceptable salt or hydrate for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD).

In a preferred embodiment of the invention said pharmaceutically composition is administered orally to patients in a dose range of 1-45 mg tid.

The further aspect of the present invention is the use of radiprodil or its pharmaceutically acceptable salt or hydrate for the preparation of a pharmaceutical composition for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD).

The further aspect of the present invention is a method for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD) in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of radiprodil in free from or pharmaceutically acceptable salt form or hydrate. In a preferred embodiment of the invention the said dosages are administered orally to patients in a dose range of 1-45 mg tid. Brief description of the drawings

Figure 1 illustrates the results of recognition of novel object at 4 months of age following acute per os 1 mg/kg atomoxetine treatment of dopamine-depleted, sham-operated and intact rats (* p<0.05 vs. sham-operated; # p<0.05 vs. 6-OHDA-lesion; ++ p<0.01 vs chance level). Recognition index is expressed as time spent with novel object in percent of time spent with both novel and familiar objects.

Figure 2 illustrates the results of recognition of novel object at 4 months of age following acute per os 5mg/kg radiprodil treatment of dopamine-depleted and sham-operated rats. Recognition index is expressed as time spent with novel object in percent of time spent with both novel and familiar objects.

Detailed description of the invention

Pharmaceutical composition comprising radiprodil or its pharmaceutically acceptable salt or hydrate for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD). Pharmaceutical composition of radiprodil or its pharmaceutically acceptable salt or hydrate dosages which are administered orally or parenterally

The pharmaceutical composition is administered orally to patients in a dose range of 1 -45 mg tid.

The use of radiprodil or its pharmaceutically acceptable salt or hydrate for the preparation of a pharmaceutical composition for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD).

The dosages of radiprodil or its pharmaceutically acceptable salts or hydrate are administered orally. The dosages of radiprodil or its pharmaceutically acceptable salts or hydrate are administered orally to patients in a dose range of 1-45 mg tid.

A method for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD) in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of radiprodil in free from or pharmaceutically acceptable salt or hydrate form. The effectiveness of radiprodil in attenuating attention and memory deficit can be shown by a number of well established tests including but not limiting to an animal model of ADHD described by van der Kooij MA and Glennon JC (Animal models concerning the role of dopamine in attention-deficit hyperactivity disorder. Neurosci Biobehav Rev. 2007;31(4):597- 618.). Neonatal 6-hydroxy-dopamine (6-OHDA) lesion in the brain was applied in rats for developing behavioral symptoms of ADHD. The beneficial effects of radiprodil were tested at adult age compared to that of atomoxetine as reference compounds known to diminish the symptoms in different animal models of ADHD and in clinic.

Male Harlan- Wistar rats were used for producing ADHD animal model at the age of 4 days (Luthman et al: Functional changes induced by neonatal 6-hydroxydopamine treatment: effects of dose levels on behavioral parameters. Behav Brain Res, 1997; 82:213-221.). Animals received 25 mg/kg desipramine (Sigma) in ΙΟμΙ/g physiological saline solution subcutaneously, 30 min prior to lesion. Under light ether anaesthesia 40-40 μg 6- hydroxydopamine (6-OHDA) were injected to both lateral ventricles in 2-2 μΐ physiological saline solution containing 0.1% ascorbic acid with a ΙΟμΙ Hamilton syringe. Control animals received the same amount of vehicle solution.

Pups were randomly distributed among foster mothers. Each mother nursed infants exclusively of the same treatment. The offspring developed undisturbed until weaning. After weaning 3 animals from the same experimental group were housed in one cage. Behavioral tests were performed at first time at the age of 30 days without treatment to check the presence of hyperactivity. The second behavioral study for checking hyperactivity and the effects of drug treatment were performed at adult age (4 months).

Sham-lesioned and 6-OHDA-lesioned rats were treated acutely with the following compounds 60 min before the behavioral tests.

- Atomoxetine Strattera (Atomoxetine HC1) Eli Lilly (100 mg atomoxetine/capsule, 370 mg material/capsule) 3.7 mg from the capsule content, containing 1 mg atomoxetine, was homogenised and dissolved in 1 ml 45% β-hydroxypropyl-cyclodextrine using glass potter. - radiprodil was dissolved in 45% hydroxypropyl-P-cyclodextrin (HPpCD) giving 2.5 mg/ml concentration. Treatment controls received the vehicle, i.e. 2 ml/kg 45% hydroxypropyl-β- cyclodextrin solution diluted in distilled water.

Table I

Animals and treatment

Experimental groups treatment per os number of animals

Series 1 (atomoxetine treatment)

Intact - 10

Sham control HPpCD 13

Sham lesion + atomoxetine 1 mg/kg 11

6-OHDA lesion control HPpCD 12

6-OHDA lesion + atomoxetine 1 mg/kg 10

Series 2 (radiprodil treatment)

Sham control 12

Sham lesion + radiprodil 5 mg/kg 10

6-OHDA lesion control HPpCD 12

6-OHDA lesion + radiprodil 5 mg/kg 10

Attention and memory function were investigated in novel object recognition in the habituated open-field apparatus (Myhrer et al: Cognitive side effects in rats caused by pharmacological agents used to prevent soman-induced lethality. Eur J Pharmacol, 2004; 483: 271-279.). The novel object recognition task originally introduced by Ennaceur and Delacour (Ennaceur, A and Delacour, J.: A new one-trial test for neurobiological studies of memory in rats. 1: behavioural data. Behav. Brain. Res.31 :47-59; 1988.) is a method to measure specific form of episodic memory in rats and mice, which has the relevance to attention as well to recognize novelty. Object recognition does not require lengthy training and does not induce high level of arousal or stress. Moreover, it is not based on usual positive and negative reinforces such as food and electric shock, which can interfere with drug effects and also with memory performance. That is why object recognition paradigm is especially suited to test the effects of pharmacological intervention.

During the first session (sample trial) two identical objects were placed into the arena keeping equal distances from the wall in an asymmetric position regarding the centre. These objects became familiar objects during the 5 min test period. After a 2 hours inter-session interval spent in the home-cage the rats were replaced into the open-field arena for the 2^nd session for another 5 min (test trial). During the second session one of the familiar objects was replaced by a novel object. Frequency (score) and duration (sec) of visiting the objects were registered. The total number and duration of visits towards both objects served for general exploratory activity, while for discriminating the novel object from the familiar one the following calculation was applied:

Duration of visits to novel object

Recognition index (%) = x 100

Duration of visits to novel + familiar objects

Comparing the experimental groups nonparametric Kruskal-Wallis analysis was used followed by multiple comparisons of mean ranks for all groups as a post hoc test using Statistica 8 software. H values, degrees of freedom and p values are indicated in the text results of post hoc test are indicated on the relevant figures as follows: * p<0.05; ** p<0.01; *** p<0.001 vs. sham lesion control, # p<0.05; ## p<0.01; ### p<0.001 vs. 6-OHDA lesion control. At first all groups were compared with Kruskall Wallis test, than the effect of neonatal treatment was checked between sham-operated and dopamine-depleted vehicle- treated rats. If the result gave significance Kruskall Wallis was applied separately on sham- operated groups and dopamine-depleted groups as well. Difference from the chance level of visiting one of the objects (50%) was estimated by paired t test and indicated on the figures: +p<0.05; ++ pO.01; +++ pO.001 vs. chance level. Recognition index of lesioned animals was around the chance level (Fig 1; t=0.35; p=0.73), while intact (t=4.1; p<0.01) and control rats significantly surpass it (t=3.8; p<0.01). Acute atomoxetine compensated well the attention deficit in dopamine-depleted rats, and increased the recognition index significantly above the chance level (t=4.4; p<0.01). There was significant difference between sham-operated and dopamine-depleted control groups (Kruskal-Wallis test: H[l,25]=4.7; p<0.05) indicating memory loss following dopamine depletion. Improvement in behavioral performance of 6-OHDA lesioned animals after atomoxetine treatment was also significant (H[l,22]=6.3; p<0.05; # p<0.05 vs. 6-OHDA- lesioned animals). Atomoxetine had no effect on the performance of control rats.

Recognition index of lesioned animals was around the chance level (Fig 2: t=0.34; p=0.74), while control rats significantly surpass it (t=3.2; p<0.01; Kruskal-Wallis analysis: H[3,44]=17.4; p<0.001). Acute radiprodil treatment resulted in significant improvement of recognition in dopamine depleted animals (post hoc test between 6-OHDA-lesioned and 6- OHDA-lesioned+rediprodil treatment ### p<0.001) and raised recognition index significantly above the chance level (t=7.5; p<0.001).

Neonatal 6-OHDA lesion in the brain of male Wistar rats resulted failure in recognizing novel object in adulthood due to attention and/or memory deficit. Atomoxetine, a drug known to decrease ADHD symptoms in clinic and also in animal models improved the performance of lesioned animals. Acute administration of radiprodil to dopamine-depleted animals had similar influence to atomoxetine: enhanced recognition of novel object. None of the drugs applied had effect on control animals during novel object recognition.

Hence, it follows that radiprodil is useful in the treatment of ADHD.

The appropriate dosage varies depending upon the compound employed, the route of administration, the patient to be treated. It is administerd orally to patients in a dose range of 1-45 mg tid. For use according to the invention radiprodil or its pharmaceutically acceptable salt or hydrate may be administered as single active agent or in combination with other active agents, in any usual manner, e.g. orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions. Moreover, the present invention provides a pharmaceutical composition comprising radiprodil or its pharmaceutically acceptable salt in association with at least one pharmaceutical carrier or diluent for use in the treatment of ADHD, authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD).

Such compositions may be manufactured in conventional manner. Unit dosage forms may contain, for example, from about 2.5 to about 45 mg of radiprodil or its pharmaceutically acceptable salt or hydrate.

Claims

Pharmaceutical composition comprising radiprodil or its pharmaceutically acceptable salt or hydrate for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive-compulsive disorders (OCD).

Pharmaceutical composition according to claim 1 wherein said radiprodil or its pharmaceutically acceptable salt or hydrate dosages are administered orally or parenterally

Pharmaceutical composition according to claim 1 wherein it is administered orally to patients in a dose range of 1-45 mg tid.

The use of radiprodil or its pharmaceutically acceptable salt or hydrate for the preparation of a pharmaceutical composition for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism,

Tourette's syndrome, and obsessive-compulsive disorders (OCD).

The use according to claim 4 wherein said radiprodil or its pharmaceutically acceptable salt or hydrate dosages are administered orally.

The use according to claim 4 wherein it is administered orally to patients in a dose range of 1-45 mg tid.

A method for the treatment and/or delay of progression of attention deficit hyperactivity disorder (ADHD), authism, Tourette's syndrome, and obsessive- compulsive disorders (OCD) in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of radiprodil in free from or pharmaceutically acceptable salt or hydrate form. A method for the treatment according to claim 7 wherein said radiprodil or its pharmaceutically acceptable salt or hydrate dosages are administered orally. A method for the treatment according to claim 7 wherein it is administered orally to patients in a dose range of 1-45 mg tid.