OA17306A - Trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin1-yl]-ethyl}-N,N-dimethylcarbamoylcyclohexylamine for treating negative symptoms of schizophrenia. - Google Patents

Abstract

The present invention relates to trans-4-{2[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl} -N,Ndimethylcarbamoyl-cyclohexylamine (cariprazine) and pharmaceutical acceptable salts and hydrates and solvates and polymorphs thereof for use in the treatment of primary negative symptoms of schizophrenia and/or predominantly negative symptoms of schizophrenia.

Description

TRANS-4-{2-[4-(2,3-DICHLOROPHENYL)-PIPERAZIN-l-YLl-ETHYL}-N,NDIMETHYLCARB AMOYL-CYCLOHEXYLAMINE FOR TREATING NEGATIVE SYMPTOMS OF SCHIZOPHRENIA

FIELD OF THE INVENTION

The présent invention relates to trans-4-(2-[4-(2,3-dichlorophenyl)piperazin-l-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine (cariprazine) and pharmaceutically acceptable salts and hydrates and solvatés and polymorphs thereof for use in the treatment of primary négative symptoms of schizophrenia and/or predominantly négative symptoms of schizophrenia.

BACKGROUND OF THE INVENTION

Schizophrenia is a prévalent, lifelong disabling psychiatrie disorder. The cardinal symptoms of schizophrenia fall into three domains such as positive symptoms (e.g., hallucination, delusion), négative symptoms (e.g., apathy, social withdrawal) and cognitive dysfunction.

The négative symptoms of schizophrenia reflect the absence or diminution of normal behaviors and functions, including problems with motivation, social withdrawal, diminished affective responsiveness, speech, and movement, contribute more to poor functional outcomes and quality of life for individuals with schizophrenia than do positive symptoms.

Distinction can be made between primary and secondary négative symptoms. Primary négative symptoms refer to the symptoms that are intrinsic to schizophrenia, while secondary négative symptoms can be conséquent upon several factors including médication side effects (such as extrapyramidal side effects) or dépression. Secondary négative symptoms may also be the conséquence of positive symptoms: social withdrawal can be caused by persecutory delusions, being distracted and preoccupied by psychotic process, or by a patient titrating down their level of social stimulation to try to minimize intrusive psychotic expériences. (Evidence-based guidelines for the pharmacologicaJ treatment of schizophrenia: recommendations from the British Association for Psychopharmacology, Journal of Psychopharmacology 0(0) 1 -54Γμ

Secondary négative symptoms would be expected to respond to treatment of the underlying cause. For example, if négative symptoms are secondary to antipsychotic treatment, the symptoms can be decreased by switching to a different antipsychotic with less extrapyramidal adverse effects or by reducing the dosage of the current antipsychotic to a level that does not produce extrapyramidal adverse effects. Similarly, if négative symptoms are secondary to depressed affect, treatments for dépression could be considered. If négative symptoms, such as social withdrawal, are caused by immersion in positive symptoms, increasing the dosage of antipsychotic médication or switching to a different antipsychotic may be warranted. If options for treating secondary causes of négative symptoms hâve failed, the options for pharmacological treatment are limited at présent

Currently atypical antipsychotics are recommended for the treatment of négative symptoms. According to the NICE Guideline (Core Interventions in the Treatment and Management of Schizophrenia in Adults in Primary and. Secondary Care, The National Institute for Health & Clinical Excellence, 2010), négative symptoms can hâve a major impact on the psychosocial and community functioning of the schizophrénie patients.

Cariprazine is specifïcally and generically disclosed in W02005/012266. WO2008/142462 discloses cariprazine for use in the treatment of schizophrenia including négative symptoms of schizophrenia. W02008/142462 is silent about the origin of négative symptoms described. As it is mentioned above, conceming the effectiveness of a treatment, it is important to distinguish the two types of the négative symptoms. Secondary négative symptoms could be treated by treating the cause but primary négative symptoms remain.

SUMMARY OF THE INVENTION

The présent invention relates to trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-l-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine and hydrates and solvatés and polymorphs and pharmaceutically acceptable salts thereof, preferably trans-4-{2[4-(2,3-dichlorophenyl)-piperazm-l-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexy!amine hydrochloride for use in the treatment of primary négative symptoms of schizophrenia and/or predominantly négative symptoms of schizophrenia/^

DETAILED DESCRIPTION OF THE INVENTION

We hâve surprisingly found that trans-4-(2-[4-(2,3-dichlorophenyl)-piperazin-lyl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine (cariprazine) is very effective in treating primary négative symptoms of schizophrenia.

Primary négative symptoms cannot be assessed as such. To evaluate the effect of a médicinal product on primary négative symptoms it is essential to exclude secondary négative symptoms as much as possible.

As it is mentioned above secondary négative symptoms are mainly the conséquence of positive symptoms, extrapyramidal side effects and dépression. The less these causes are présent the greater the likelihood that primary négative symptoms can be assessed.

For example when négative symptoms are dominant and positive symptoms are presented less prominently (in case of patients with predominantly négative symptoms), it can be presumed that négative symptoms secondary to positive symptoms are less déterminant than primary négative symptoms.

According to the clinical study described in Example we hâve surprisingly found that primary négative symptoms of schizophrenia can be treated effectively with cariprazine. In the clinical study beside the ITT (intent to treat) population which included the total number of the patients, a subgroup was identified including patients with predominantly négative symptoms. This subgroup was identical with the patient subpopulation showing ’ severe négative symptoms defined by Lenert et al. (Schizophrenia Research 71 (2004) 155165). Patients showing severe négative symptoms were separated into two groups: State 4 and State 6 (définitions are desribed in Example). State 4 and State 6 together represent the patient subpopulation with predominantly négative symptoms.

As it is mentioned above if négative symptoms are secondary to positive symptoms négative symptoms tend to improve along with the positive symptoms. In case of patients with primary négative symptoms the effect of alleviating négative symptoms can be considered as a direct effect and not as a secondary effect due to the improvement în positive symptoms.If the improvement in négative symptoms is mainly secondary to the improvement in positive symptoms, the improvement on the PANSS factor score for négative symptoms will expected to decrease or not change in the subpopulation representing patients with predominantly négative symptoms compared to the ITT population.

Comparing the improvements on the PANSS factor score for négative symptoms in the ΓΓΤ population and the subpopulation representing patients with predominantly négative symptoms (Figure 1-4), we hâve surprisingly found that while there was no différence in risperidone’s efficacy on négative symptoms comparing the ΓΓΤ population to the patient subpopulation showing prédominant négative symptoms, cariprazine achieved numerically higher improvement on the PANSS factor score for négative symptoms in the subpopulation with prédominant négative symptoms compared to its’ effect in the ITT population.

As it was mentioned above extrapyramidal symptoms (EPS) are common side effects of antipsychotic médications. EPS may also cause secondary négative symptoms; hence they could bias the observed effect of cariprazine in négative symptoms. According to their experienced extrapyramidal side effects a subgroup of patients without EPS was selected from the group of patients with predominantly négative symptoms treated with cariprazine. Comparing the efficacy of cariprazine in these groups, it does not seem to be influenced by the treatment emergent EPS (Figure 5).

As it was mentioned above dépression can also lead to secondary négative symptoms. In the study, described in Example, the subgroup of patients with predominantly négative symptoms in ail cariprazine treatment arms tended to hâve low to moderate dépressive symptoms. It means that they had a maximum score of 4 for question PANSS G6, which rates dépression on a scale of 1-7.

The results of this study clearly shows that cariprazine has a direct effect on négative symptoms of schizophrenia. So cariprazine has an effect on primary négative symptoms of schizophrenia.

It has been now discovered that trans-4-{2-[4-(2,3-dichlorophenyl)piperazin-1 -yI]-ethyl} -Ν,Ν-dimethylcarbamoyl-cycIohexylamine and pharmaceutically acceptable salts and hydrates and solvatés and polymorphs thereof are useful in the treatment of primary négative symptoms of schizophrenia and/or predominantly négative symptoms of schizophrenia.

Phaimaceutically acceptable salts include those obtained by reacting the main compound, fonctioning as a base with an inorganic or organic acid to form a sait, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalîc acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable salts also include those in which the main compound fonctions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnésium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Altematively, alkali and alkaline earth métal salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

The following are forther examples of acid salts that can be obtained by reaction with inorganic or organic acids: acétates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycérophosphates, hemisulfates, heptanoates, hexanoates, fomarates, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.

In a preferred embodiment, the pharmaceutically acceptable sait is a hydrochloride sait.

Some of the compounds usefol in the présent invention can exist in different polymorphie forms. As known in the art, polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or polymorphie species. A polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphie forms of that compound molécule in the solid state. Polymorphie forms of any given compound are defïned by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds. The use of such polymorphs is within the scope of the présent invention.

Some of the compounds useful in the présent invention can exist in different solvaté forms. Solvatés of the compounds of the invention may also form when solvent molécules are incorporated into the crystalline lattice structure of the compound molécule during the crystallization process. For example, suitable solvatés include hydrates, e.g., monohydrates, dihydrates, sesquihydrates, and hemihydrates. The use of such solvatés is within the scope of the présent invention.

Furthermore, the présent invention particulariy relates to the use of trans-4- {2-(4-(23dichlorophenyl)-piperazin-l -yl]-ethy 1} -Ν,Ν-dimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof, more particulariy to the use of trans-4-{2-[4-(23dichlorophenyl)-piperazin-1 -yl] -ethyl} -Ν,Ν-dimethy Icarbamoy 1-cyclohexylamine hydrochloride for use in the treatment of primary négative symptoms of schizophrenia.

DEFINITIONS

The term “predominantly négative symptoms” means that severe négative symptoms are dominant and PANSS factor score for négative symptoms is > 24.

The term “change from baseline” refers to the change of the value of the PANSS factor score for négative symptoms compared to the value registered before treatment started (at the baseline visit). The values were calculated using least squares method. The least squares mean (LSM) values resulted from the analysis of covariance (ANCOVA) model with treatment group and study center as factors and the baseline PANSS factor score of négative symptoms as the covariate.

Positive and Négative Syndrome Scale (PANSS)

The Positive and Négative Syndrome Scale (PANSS) is a medical scale used for measuring symptom réduction of schizophrenia patients. The scale has seven positive-symptom items (positive subscale), seven negativesymptom items (négative subscale) and, 16 general psychopathology symptom items (general psychopathology subscale) . Each item is rated on a scale from 1 (symptom not présent) to 7 (symptoms extremely severe). Objectivité and standardization of the scale is optimized by a tightly structured interview. (Kay et al, Schizophr. Bull., 13, 261-76, 1987)

PANSS factor scores

PANSS factor scores are used in our clinical studies to asses négative, positive and cognitive symptoms of schizophrénie. Each of them is a sum of scores for certain items of the PANSS scale. (Lenert et al.: Schizophrenia Research 71 (2004) 155-165)

PANSS factor score for négative symptoms: Sum of scores for items 1,

2, 3, 4, and 6 in négative subscale: blunted affect, emotional withdrawal, poor rapport, passive social withdrawal, lack of spontaneity; and items 7 and 16 in general psychopathology subscale: motor retardation, and active social avoidance. Higher scores indicate worsening.

PANSS factor score for positive symptoms: Sum of scores for items 1,

3, 5, 6 in positive subscale: delusion, hallucinatory behavior, grandiosity, suspiciousness; and item 9 in general psychopathology subscale: unusual thought content. Higher scores indicate worsening.

PANSS factor score for cognitive symptoms: Sum of scores for items 5, 10, 11, 12, 13 and 15 in general psychopathology subscale: mannrisms and posturing, disorientation, poor attention, lack of judgement and insight, disturbance of volition, préoccupation; and item 2 in positive subscale: conceptual disorganization; and items 5, 7 in négative subscale: difficulty in abstract thinking, stereotyped thinking. Higher scores indicate worsening.

DESCRIPTION OF FIGURES

Figure 1: Improvements on the PANSS factor score for négative symptoms in the ITT population and the subpopulation representing patients with predominantly négative symptoms in Rispéridone (4 mg/day) treatment arm.

Figure 2: Improvements on the PANSS factor score for négative symptoms in the ITT population and the subpopulation representing patients with predominantly négative symptoms in Cariprazine (1.5 mg/day) treatment arm. A

Figure 3: Improvements on the PANSS factor score for négative symptoms in the ITT population and the subpopulation representing patients with predominantly négative symptoms in Cariprazine (3 mg/day) treatment arm.

Figure 4: Improvements on the PANSS factor score for négative symptoms in 5 the ITT population and the subpopulation representing patients with predominantly négative symptoms in Cariprazine (4.5 mg/day) treatment arm.

Figure 5: Effect of extrapyramidal symptoms on the change of PANSS factor score for négative symptoms at week 6. Two groups are compared: patients of the Caripazine (1.5 mg/day, 3 mg/day, 4.5 mg/day) treatment arms, patients 10 without EPS of the Caripazine (1.5 mg/day, 3 mg/day, 4.5 mg/day) treatment arms.

The following example is merely illustrative of the présent invention and should not 15 be construed as limiting the scope of the invention in any way as many variations and équivalents that are encompassed by the présent invention will become apparent to those skilled in the art upon reading the présent disclosure.

EXAMPLE

A représentative clinical study was conducted as an international, multicenter, double20 bind, placebo- and risperidone-controlled, fixed-dose trial. The objective of the study was to evaluate the safety and efficacy of cariprazine fixed doses in patients with schizophrenia.

A total of 732 patients were selected using criteria that includes patients who (i) currently meet or hâve met in the past the Diagnostic and Statistîcal Manual of Mental Disorders, Fourth Edition, Text Révision (DSM-IV-TR) criteria for schizophrenia (295.30 Paranoid Type, 25 295.10 Disorganized Type, 295.20 Catatonie Type, or 295.90 Undifferentiated Type) based on the Structured Clinical Interview for DSM-IV (SCID), (ii) hâve a PANSS total score > 80 and < 120, (iii) hâve a score > 4 on Clinical Global Impression-Severity scale (iv) hâve a score > 4 on at least 2 of the following 4 PANSS positive symptoms: delusions, hallucinatory behavior, conceptual disorganization, and suspiciousness/persecution.

During a 6 week period, 3 doses of cariprazine (1.5 mg/day, 3 mg/day, 4.5 mg/day) was compared to placebo and to an effective dose of rispéridone (4.0 mg/day).

Beside the ΓΓΤ (intent to treat) population which included the total number of the patients, a subgroup was identified including patients with predominantly négative symptoms. This subgroup was identical with the patient subpopulation showing severe négative symptoms defined by Lenert et al. (2004). Lenert et al. divided schizophrenia into 8 states, each based on 5 a three-axis scale (PANSS positive, négative and cognitive factor scores). Patients showing severe négative symptoms were separated into two groups: State 4 (severe with négative dominance of symptoms) and State 6 (severe with négative and cognitive symptoms). The définition of State 4 is the following:

• PANSS factor score for négative symptoms is > 24 · PANSS factor score for positive symptoms is < 19 • PANSS factor score for cognitive symptoms is < 26

The définition of State 6 is the following:

• PANSS factor score for négative symptoms is > 24 • PANSS factor score for positive symptoms is < 19 • PANSS factor score for cognitive symptoms is > 27|

8 MAI 2015

Claims (4)

1. Trans-4-{2-(4-(2,3-dich!orophenyl)-piperazin-l-yl]-ethyl)-N,Ndimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts and hydrates and solvatés and polymorphs thereof for use in treating primary négative symptoms of schizophrénie

2. Trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-l-yl]-ethyl}-N,Ndimethylcarbamoyl-cyclohexylamine for use according to claim 1, in the form of trans-4{2-[4-(2,3-dichlorophenyl)-piperazin-l-yI]-ethyl}-N,N-dimethyIcarbamoylcyclohexylamine hydrochloride and/or hydrates and/or solvatés and/or polymorphs thereof.

3. Trans-4-(2-[4-(2,3-dichlorophenyl)-piperazin-l-yl]-ethyl}-N,Ndimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts and hydrates and solvatés and polymorphs thereof for use in treating predominantly négative symptoms in schizophrénie

4. Trans-4- (2-[4-(2,3-dichlorophenyl)-piperazin-1 -yl]-ethyl} -N,Ndimethylcarbamoyl-cyclohexylamine for use according to claim 3, in the form of trans-4{2-[4-(23-<lichlorophenyl)-piperazm-l -yl]-ethyl] -N,N-dimethylcarbamoylcyclohexylamine hydrochloride and/or hydrates and/or solvatés and/or polymorphs thereof. d*