BR-PI0811199-B1 - NEW PIPERAZINE SALTS AS D3/D2 ANTAGONISTS

Abstract

NEW PIPERAZINE SALTS AS D3/D2 ANTAGONISTS. The present invention relates to new monochloride, dichloride, monobromide, maleate and methanesulfonate salts of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine and/or their hydrates and/or solvates. Furthermore, the invention relates to the process for preparing the salts and their hydrates and/or solvates, and their use in the treatment and/or prevention of conditions requiring dopamine receptor modulation and to pharmaceutical compositions containing them.

Inventors

ÉVA ÁGAINÉ CSONGOR
Lászlò Czibula
Ferenc Sebök
György Domány
István Greiner

Assignees

RICHTER GEDEON NYRT

Dates

Publication Date: 20260317
Application Date: 20080513
Priority Date: 20070511

Claims (6)

1. Anhydrous trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine hydrochloride (Form I), characterized by having: - an infrared spectrum substantially as represented in Figure 1, comprising characteristic peaks at 3321, 2931, 2914, 2466, 1652, 1526, 956, 784 and 715 cm-1 ± 4 cm-1; - a Raman spectrum substantially as represented in Figure 2, comprising characteristic peaks of 3070, 2986, 2969, 2933, 2914, 2864, 2850, 1578, 1458, 1052 and 475 cm-1 ± 4 cm-1; and - a polycrystalline X-ray diffraction pattern substantially as described in Figure 3, comprising peaks of 6.6; 7.3; 13.2; 14.2; 14.6; 16.9; 21.1; 22.4; 24.8; 26.5 and 26.6 ± 0.2 degrees 2θ.
2. Process for the preparation of a crystalline form as defined in claim 1, characterized in that the base trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine is suspended or dissolved in a suitable solvent or mixture of solvents and then an acid or a salt thereof prepared with a base weaker than the base trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine, or a solution thereof, is added, and optionally, the reaction mixture is concentrated and/or cooled and then the product obtained is isolated by filtration.
3. Pharmaceutical composition characterized by consisting of a crystalline form as defined in claim 1 and one or more pharmaceutically acceptable ingredients.
4. Use of a crystalline form as defined in claim 1, characterized in that it is for the production of a medicament for the treatment and/or prevention of conditions requiring the modulation of a dopamine receptor.
5. Use according to claim 4, characterized in that the dopamine receptor is the D3 dopamine receptor and/or the D2 dopamine receptor.
6. Use, according to claim 4, characterized in that the condition requiring dopamine receptor modulation is selected from among schizoaffective disorders, cognitive deficit accompanied by schizophrenia, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism), depression, anxiety, and drug abuse.

Description

FIELD OF THE INVENTION The present invention relates to novel salts of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine, to processes for their preparation for use in the treatment and/or prevention of conditions requiring modulation of dopamine receptors, and to pharmaceutical compositions containing the same. BACKGROUND OF THE INVENTION Hungarian Patent Report No. P0302451 discloses (thio)-carbamoyl-cyclohexane derivatives that are preferred ligands of the D3/D2 dopamine receptor subtype. A specific compound disclosed in this patent is trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine, which acts as a dopamine receptor antagonist, particularly a D3/D2 receptor antagonist, and is useful in the treatment and prevention of pathological conditions requiring modulation of dopamine receptors. In general, pharmaceutical compositions containing an active agent are required to have adequate physical, physicochemical, and chemical properties. An important property of the active agent is its solubility, particularly its water solubility. When the active agent has insufficient water solubility, it must usually be converted into a form with appropriate solubility properties, for example, a salt and/or a solvate of the active agent. However, in the case of salts and/or solvates, only pharmaceutically acceptable salts and/or solvates of the active agent may be used in the preparation of pharmaceutical compositions. Furthermore, for industrial-scale synthesis to be successful, the active agent must possess properties that facilitate its handling and large-scale production. In many cases, a crude active agent product is recovered from a reaction mixture through a complicated process, usually involving multiple steps, which can decrease yields and significantly increase production costs. Therefore, also for economic reasons, the active agent must be easy to handle and readily isolable. Handling properties also have a considerable effect on the final purity of the active agent, which is one of the most important factors to consider in the pharmaceutical industry. Another matter of great importance is the stability of the active agent form used. The durability of a pharmaceutical composition, which includes the stability of the active agent itself, is of great importance, especially for quality control purposes. It is known that these properties of the active agent can be improved by choosing an appropriate salt form. However, selecting a suitable salt for a specific active agent is not always straightforward, since the properties of salts of different compounds formed with the same salt-forming agent can differ greatly. The base form of the salts according to this invention, namely, the base trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine, is substantially insoluble in water. Therefore, our objective was to obtain a form of the trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine compound that would meet all the solubility, handling, and stability requirements mentioned above. Brief description of the invention. During our experiments, we were surprised to discover that, among the numerous salts described in the technical field, monochloride, dichloride, monobromide, maleate, and methanesulfonate salts exhibit excellent properties of stability, isolability, handling, and solubility. Thus, the present invention relates to novel monochloride, dichloride, monobromide, maleate and methanesulfonate salts of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine and/or their hydrates and/or solvates, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the therapy and/or prevention of conditions requiring modulation of dopamine receptors, particularly D3/D2 receptors. Examples of conditions that require dopamine receptor modulation include, for example, psychotic states (e.g., schizophrenia, schizoaffective disorders, etc.), drug abuse (e.g., alcohol, cocaine, nicotine, opiate abuse, etc.), cognitive impairment accompanied by schizophrenia, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorders, childhood hyperactivity disorders, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), anxiety disorders, sexual dysfunction, sleep disorders, vomiting, aggression, autism. Detailed Description of the Invention The present invention relates to monochloride, dichloride, monobromide, maleate and methanesulfonate salts of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine and/or their hydrates and/o