Maleate salt of 3-bromo-N-{ (2S) -2- (4-fluorophenyl) -4- [3- (4- acetylpiperazin-1-yl) azetidin-1-yl] butyl} -methyl-5- (trifluoromethyl)benzamide for the treatment of gastrointestinal disorders

Field of the invention

The present invention relates to 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4- acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate and crystalline forms thereof. The present invention also relates to the use of said salt and crystalline forms thereof for the treatment of gastrointestinal disorders, pharmaceutical compositions containing it as well as processes for the preparation of the salt and novel crystalline forms thereof.

Background of the invention

The neurokinins, also known as the tachykinins, comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems. The three principal tachykinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB). At least three receptor types are known for the three principal tachykinins. Based upon their relative selectivities favouring the agonists SP, NKA and NKB, the receptors are classified as neurokinin 1 (NKi), neurokinin 2 (NK ₂ ) and neurokinin 3 (NK ₃ ) receptors, respectively.

There is a need for an orally active NK receptor antagonist for the treatment of e.g. respiratory, cardiovascular, neuro, pain, oncology, inflammatory and/or gastrointestinal disorders. In order to increase the therapeutic index of such therapy it is desirable to obtain such a compound possessing no or minimal toxicity as well as being selective to said NK receptors. Furthermore, it is considered necessary that said medicament has favourable pharmacokinetic and metabolic properties thus providing an improved therapeutic and safety profile such as lower liver enzyme inhibiting properties.

It is well known that severe problems such as toxicity may occur if plasma levels of one medication are altered by the co-administration of another drug. This phenomenon - which is named drug-drug interactions - could happen if there is a change in the metabolism of one drug caused by the co-administration of another substance possessing liver enzyme

inhibiting properties. CYP (cytochrome P450) 3A4 is the most important enzyme in the human liver as a majority of oxidised drugs have been biotransformed by this enzyme. Accordingly, it is undesirable to employ a medication having a significant degree of such liver enzyme inhibiting properties. It has been found that many NK receptor antagonists known in the art inhibit the CYP3A4 enzyme to a certain level and consequently there is a possible risk if high doses of those compounds are being used in therapy. Thus, there is a need for a novel NK receptor antagonist with improved pharmacokinetic properties. The present invention provides compounds with CYP3A4 enzyme inhibiting properties at a low level, as comparatively high IC50 values are obtained in a CYP3 A4 inhibiting assay. Said method for determining CYP3A4 inhibition is described in Bapiro et al; Drug Metab. Dispos. 29, 30-35 (2001).

It is well known that certain compounds may cause undesirable effects on cardiac repolarisation in man, observed as a prolongation of the QT interval on electrocardiograms (ECG). In extreme circumstances, this drug-induced prolongation of the QT interval can lead to a type of cardiac arrhythmia called Torsades de Pointes (TdP; Vandenberg et al. hERG K ⁺ channels: friend and foe. Trends Pharmacol Sci 2001; 22: 240-246), leading ultimately to ventricular fibrillation and sudden death. The primary event in this syndrome is inhibition of the rapid component of the delayed rectifying potassium current (IKr) by these compounds. The compounds bind to the aperture- forming alpha sub-units of the channel protein carrying this current. The aperture-forming alpha sub-units are encoded by the human ether-a-go-go-related gene (hERG). Since IKr plays a key role in repolarisation of the cardiac action potential, its inhibition slows repolarisation and this is manifested as a prolongation of the QT interval. Whilst QT interval prolongation is not a safety concern per se, it carries a risk of cardiovascular adverse effects and in a small percentage of people it can lead to TdP and degeneration into ventricular fibrillation.

In particular, it is desirable that the NK receptor antagonist has a suitable balance of pharmacodynamic and pharmacokinetic properties to make it therapeutically useful. In addition to having sufficient and selective potency, the NK receptor antagonist needs to be balanced with regard to relevant pharmacokinetic properties. Thus, it is necessary that the NK antagonist has: a) sufficiently high affinities at the different NK receptors, b)

pharmacokinetic properties (absorption, distribution and elimination properties) that makes it possible for the drug to act at the targeted NK receptors in the periphery as well as in the CNS. For instance, the NK receptor antagonist needs to have sufficiently high metabolic stability, c) sufficiently low affinities to different ion channels, such as the hERG-encoded potassium channel in order to obtain a tolerable safety profile and d) liver enzyme (such as CYP3A4) inhibiting properties at a low level to prevent drug-drug interactions. Furthermore, in order to enhance the efficacy of the NK receptor antagonist, it is beneficial to have an NK antagonist with a long-lasting competitive mode of action at the receptor.

EP 0625509, EP 0630887, WO 95/05377, WO 95/12577, WO 95/15961, WO 96/24582, WO 00/02859, WO 00/20003, WO 00/20389, WO 00/25766, WO 00/34243, WO 02/51807 and WO 03/037889 disclose piperidinylbutylamide derivatives, which are tachykinin antagonists.

"4-Amino-2-(aryl)-butylbenzamides and Their Conformationally Constrained Analogues. Potent Antagonists of the Human Neurokinin-2 (NK2) Receptor", Roderick MacKenzie, A-, et al, Bioorganic & Medicinal Chemistry Letters (2003), 13, 2211-2215, discloses the compound N-[2-(3, 4-dichlorophenyl)-4-(3-morpholin-4-ylazetidin-l-yl)butyl]-λ /- methylbenzamide which was found to possess functional NK ₂ receptor antagonistic properties.

WO 96/05193, WO 97/27185 and EP 0962457 disclose azetidinylalkyllactam derivatives with tachykinin antagonist activity.

EP 0790248 discloses azetidinylalkylazapiperidones and azetidinylalkyloxapiperidones, which are stated to be tachykinin antagonists.

WO 99/01451 and WO 97/25322 disclose azetidinylalkylpiperidine derivatives claimed to be tachykinin antagonists.

EP 0791592 discloses azetidinylalkylglutarimides with tachykinin antagonistic properties.

WO2004/110344 A2 discloses dual NKl, 2 antagonists and the use thereof.

An object of the present invention was to provide a novel salt of a neurokinin antagonist useful in therapy, having well-balanced pharmacokinetic, pharmacodynamic and solid state properties.

Brief description of the drawings

Figure 1 is an X-ray powder diffractogram of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3- (4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide original form (bottom) and the form obtained by suspending 3-bromo-λ/-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate in water or acetone (top).

Description of the invention

It has surprisingly been found that 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4- acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate can exist in several forms.

One aspect of the present invention is the original form of 3-bromo-λ/-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate .

The original form of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin -l- yl)azetidin-l -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate is characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d-values (d-value: the spacing between successive parallel hkl planes in a crystal lattice):

Original form I Original form I Original form d-value Relative I d-value Relative I d-value Relative

For the relative intensities the following definitions are used:

A further aspect of the invention is an ethanol solvate of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate, characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d- values (d- value: the spacing between successive parallel hkl planes in a crystal lattice):

A further aspect of the invention is an acetonitrile solvate of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate, characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d- values (d- value: the spacing between successive parallel hkl planes in a crystal lattice):

A further aspect of the invention is an chloroform solvate of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yl]butyl} -N-methγl-5- (trifluoromethyl)benzamide maleate, characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d- values (d- value: the spacing between successive parallel hkl planes in a crystal lattice):

A further aspect of the invention is an obtained form of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate, characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d- values (d- value: the spacing between successive parallel hkl planes in a crystal lattice):

The compounds according to the present invention is useful for the prevention or treatment of respiratory, cardiovascular, neuro, pain, oncology and/or gastrointestinal disorders. Examples of such disorders are asthma, allergic rhinitis, pulmonary diseases, cough, cold, inflammation, chronic obstructive pulmonary disease, airway reactivity, urticaria, hypertension, rheumatoid arthritis, edema, angiogenesis, pain, migraine, tension headache, psychoses, depression, anxiety, Alzheimer's disease, schizophrenia, Huntington's disease, bladder hypermotility, urinary incontinence, eating disorder, manic depression, substance

dependence, movement disorder, cognitive disorder, obesity, stress disorders, micturition disorders, mania, hypomania and aggression, bipolar disorder, cancer, carcinoma, fibromyalgia, non cardiac chest pain, gastrointestinal hypermotility, gastric asthma, Crohn's disease, gastric emptying disorders, ulcerative colitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), emesis, gastric asthma, gastric motility disorders, functional dyspepsia or gastro-esophageal reflux disease (GERD).

It is further provided a pharmaceutical composition comprising 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate or crystalline forms thereof according to the present invention, as active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other active pharmaceutical ingredients. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compound according to the present invention may be formulated by means known in the art into the form of, for example, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the compound according to the present invention, the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.

The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.

Typically, unit dosage forms will contain about 1 mg to 500 mg of a compound of the according to this invention. For example, a tablet or capsule for oral administration may conveniently contain up to 500 mg (and typically 5 to 100 mg) of the compound according to the present invention. In another example, for administration by inhalation, the compound of the present invention may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of the compound of the present invention may be used.

In the practice of the invention, the most suitable route of administration as well as the therapeutic dose will depend on the nature and severity of the disease to be treated. The dose, and dose frequency, may also vary according to the age, body weight and response of the individual patient.

The compound according to the present invention may be further processed before formulation into a suitable pharmaceutical formulation. For example, the 3-bromo-7V- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yl]butyl} -7V-methyl-5- (trifiuoromethyl)benzamide maleate or crystalline forms thereof may be milled or ground into smaller particles.

For the avoidance of doubt, "treatment" includes the therapeutic treatment, as well as the prophylaxis, of a condition.

The presence of additional substances in a sample, like pharmaceutical excipients, to be characterised by X-ray powder diffraction can mask some of the peaks in the above characterized compound. This fact alone can of course not demonstrate that the compound is not present in the sample. Under such circumstances due care must be used and the presence of substantially all main peaks in the X-ray powder diffraction pattern might suffice to characterize the compound. It is thus preferred to analyse the compound of the present invention without the presence of additional substances.

Examples

The following abbreviations are used in the experimental: DIPEA (N, N- diisopropylethylamine), DMF (N,N-dimethylformamide), TBTU (AWN'N-tetramethyl-O- (benzotriazol-l-yl)uronium tetrafluoroborate), THF (tetrahydrofuran) and RT (room temperature).

Synthesis of 3-bromo-iV- {(26 ^f )-2-(4-fluorophenyl)-4-r3-(4-acetylpiperazin- 1 -vDazetidin- 1 - yllbutvU-λ/-methyl-5-(trifluoromethyl)benzamide

l-acetyl-4-azetidin-3-ylpiperazine dihydrochloride (see WO 96/05193; 5.528 g, 2.754 g, 0.0107 mol, 1.3 eq) was dissolved in MeOH (25.0 ml, 6.76 vol) at 25 to 30 ⁰ C. Triethylamine (2.538 g, 0.0248 mol, 3.0 eq) was added, followed by the addition of 3- bromo-N-[(25)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(tri fluoromethyl)benzamide (4.45 g, 0.00827 mol, 1.0 eq) solution in MeOH (25.0 ml, 6.76 rel vol) and triethylamine (0.845 g, 0.00827 mol, 1.0 eq). NaB(O ₂ CCH ₃ ) ₃ H (2.676 g, 0.0124 mol, 1.5 eq) was added in three lots at an interval of 15 to 30 minutes. After completion of the reaction, H ₂ O (0.148 g, 0.00827 mol, 1.0 eq) was added and the reaction mass concentrated under reduced pressure to remove MeOH at 48-50 ⁰ C. The residue was dissolved in 2-MeTHF (50.0 ml, 13.5 rel vol). The organic layer was washed with 10% NaHCO ₃ solution (25.0 ml x 2 times). The reaction mass was concentrated under reduced pressure to remove 2- MeTHF at 48-50 ⁰ C. The crude product was dissolved in isopropanol (20.0 ml, 5. Orel vol). ¹ H NMR (500 MHz, CDCl ₃ ): 1.4-1.8 (cm, 2H), 2.0 (s, 3H), 2.1-3.8 (cm, 21H), 6.8-7.4 (cm, 6H), 7.7 (s, IH); LCMS: m/z 614 (M+l) ⁺ .

Synthesis of 3-bromo-N-r(2y)-2-(4-fluorophenvπ-4-oxobutyl1-N-methyl-5-

(trifluoromethyl)benzamide

(a) 3-Bromo-N-[(2S)-2-(4-fluorophenyl)pent-4-en-l-yl]-N-methyl-5 - (trifluoromethyl)benzamide

To a solution of [(25)-2-(4-fluorophenyl)pent-4-en-l-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 0.54 g, 2.8 mmol) and 3-bromo-5-trifluoromethyl benzoic acid (0.81 g, 3.0 mmol) in DMF (7 mL) was added TBTU (0.96 g, 3.0 mmol) and DIPEA (1.41 g, 10.9 mmol). The reaction mixture was stirred under nitrogen overnight at RT and then partitioned between ethyl acetate and an aqueous NaHCO ₃ solution. The aqueous phase was extracted trice with ethyl acetate. The combined organic solutions were washed trice with water and then dried by a phase separator column. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (ethyl acetate - heptane 10% to 17%). There was obtained 0.86 g (68%) of 3-bromo-N-[(25)-2-(4- fluorophenyl)pent-4-en-l-yl]-λ/-methyl-5-(trifluoromethyl)b enzamide. ¹ H NMR (500

MHz, CDCl ₃ ): 2.1-3.8 (cm, 8H), 4.9-5.1 (m, 2H), 5.5-5.8 (m, IH), 6.8-7.4 (cm, 6H), 7.8 (s, IH).

(b) 3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5- (trifluoromethyl)benzamide

To a solution of 3-bromo-λ/-[(25)-2-(4-fluorophenyl)pent-4-en-l-yl]-λ/-meth yl-5- (trifluoromethyl)benzamide (0.86 g, 1.9 mmol) in acetone (45 mL) were added OsO ₄ (2.5% in t-butyl alcohol, 0.49 mL, 0.039 mmol) and 4-methylmorpholine-4-oxide (0.41 g, 3.5 mmol). The solution was stirred under nitrogen at RT overnight and then an aqueous solution OfNaHSO ₃ (39%, 45 mL) was added. The mixture was stirred for 2 h, diluted with water and then extracted twice with methylene chloride. The combined organic solutions were separated by means of a phase separator column and the solvent was removed by evaporation. The residue (1.08 g) was dissolved in THF (18 mL) and water (4.5 mL) and to the resultant solution was added NaIO ₄ (0.73 g, 3.4 mmol). The mixture was stirred under nitrogen overnight at RT. The mixture was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride

and then the combined organic solutions were washed with brine and separated by means of a phase separator column. The solvent was removed by evaporation and there was obtained 0.78 g (90%) of the title compound. ¹ R NMR (500 MHz, CDCl ₃ ): 2.4-4.4 (cm, 8H), 6.8-7.8 (cm, 7H), 9.8 (s, IH); LCMS: m/z 447 (M-I) ⁺ .

Original form of 3-bromo-iV- {(26 ^f )-2-(4-fluorophenyl)-4-r3-(4-acetylpiperazin- 1 - vDazetidin- 1 -yllbutyl} -A/-methyl-5-(trifluoromethyl)benzamide maleate

Maleic acid (0.965 g, 0.0081 mol, 1.96 eq) was added to above isopropanol solution followed by addition of isopropanol (10.0 ml, 5.0 rel vol) at 25 to 30 ⁰ C. The slurry was stirred for 30-40 min. The slurry mass was filtered and the filtered cake washed with isopropanol at 25 to 30 ⁰ C. The material was transferred to a tray and dried under reduced pressure at 45 to 50 ⁰ C. The 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin - l-yl)azetidin-l-yl]butyl}-λ/-methyl-5-(trifluoromethyl)benz amide maleate was obtained as a partially crystalline white powder.

The original form of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin -l- yl)azetidin-l-yl]butyl}-λ/-methyl-5-(trifluoromethyl)benzam ide maleate is characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d-values (d-value: the spacing between successive parallel hkl planes in a crystal lattice):

The peaks, identified with d- values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of the original form of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate, shown in the bottom of Figure 1. The relative intensities are less reliable and instead of numerical values the following definitions are used:

* The relative intensities are derived from diffractograms measured with variable slits.

Slurries of maleate salt of 3-bromo-AM(2ιSy2-(4-fluorophenyl)-4-r3-(4-acetylpiperazin-l - vDazetidin- 1 -yllbutyl} -A/-methyl-5-(trifluoromethyl)benzamide

About 40 mg of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin -l- yl)azetidin-l -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate was suspended in about 500 μl of ethanol, acetonitrile, chloroform, water and acetone. Crystal forms of three solvates, individually different, were obtained from the suspensions of 3-bromo-N-{(25)-2- (4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate in ethanol, acetonitrile and chloroform respectively.

The ethanol solvate of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin -l- yl)azetidin-l-yl]butyl}-λ/-methyl-5-(trifluoromethyl)benzam ide maleate is characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d-values (d-value: the spacing between successive parallel hkl planes in a crystal lattice):

The peaks, identified with d-values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4- acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate. The relative intensities are less reliable and instead of numerical values the following definitions are used:

* The relative intensities are derived from diffractograms measured with variable slits.

The acetonitrile solvate of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin -l- yl)azetidin-l-yl]butyl}-λ/-methyl-5-(trifluoromethyl)benzam ide maleate is characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d-values (d-value: the spacing between successive parallel hkl planes in a crystal lattice):

The peaks, identified with d- values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4- acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate. The relative intensities are less reliable and instead of numerical values the following definitions are used:

* The relative intensities are derived from diffractograms measured with variable slits.

The chloroform solvate of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin -l- yl)azetidin-l-yl]butyl}-λ/-methyl-5-(trifluoromethyl)benzam ide maleate is characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d-values (d-value: the spacing between successive parallel hkl planes in a crystal lattice):

The peaks, identified with d-values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4- acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate. The relative intensities are less reliable and instead of numerical values the following definitions are used:

* The relative intensities are derived from diffractograms measured with variable slits.

A further crystalline form is obtained by suspending 3-bromo-λ/-{(25)-2-(4-fluorophenyl)- 4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate in water or acetone. The obtained form of 3-bromo-λ/-{(25)-2-(4-fluorophenyl)-4- [3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -λ/-methyl-5-(trifluoromethyl)benzamide maleate is characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d-values (d-value: the spacing between successive parallel hkl planes in a crystal lattice):

The peaks, identified with d-values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of the obtained form of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide maleate, shown in the top of Figure 1. The relative intensities are less reliable and instead of numerical values the following definitions are used:

* The relative intensities are derived from diffractograms measured with variable slits.

The form of 3-bromo-7V- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 - yl]butyl}-λ/-methyl-5-(trifluoromethyl)benzamide maleate described above (obtained by suspending 3-bromo-7V- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 - yl]butyl}-λ/-methyl-5-(trifluoromethyl)benzamide maleate in water or acetone) was also obtained by heating the original sample to 130 ⁰ C as well as by storing the original form at 40°C/75%RH for three months.

X-ray powder diffractometry (XRPD)

XRPD experiments were performed on a D8 Advance diffractometer (Bruxer AXS GmbH, Karlsruhe, Germany) with Bragg-Brentano geometry, equipped with a VANTEC-1 position sensitive detector (PSD). Nickel- filtered Cu K _α radiation was used. The samples, approx. 10 mg, were mounted on a zero-background holder (silicon crystal). Data was collected using continuous scan mode in the range 1-50° 2θ, with a step size of 0.017° and a step time of 0.5 sec. A variable (V20) divergence slit and a detector slit of 12 mm, corresponding to a 3.47° wide detector window, were applied.

Hot-stage XRPD was performed on the instrument described above, using similar settings with an accompanying MRI chamber (Bruxer AXS GmbH, Karlsruhe, Germany), connected to an Ansyco temperature controller.