WO2008118091A1

WO2008118091A1 - A fumarate salt of 3-bromo-n-{ (2s) -2- (4 -fluorophenyl) -4- [3- (4-acetylpiperazin-l-yl) azetidin-1-yl] butyl} -n-methyl-5- (trifluoromethyl)benzamide for the treatment of gastrointestinal disorders

Info

Publication number: WO2008118091A1
Application number: PCT/SE2008/050342
Authority: WO
Inventors: Marlene Fredenwall; Carl-Gustav Sigfridsson
Original assignee: Albireo Ab
Priority date: 2007-03-28
Filing date: 2008-03-27
Publication date: 2008-10-02

Abstract

The present invention relates to 3-bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(4- acetylpiperazin-1-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamide fumarate 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.

Description

umara e sa o - romo- - - - - uorop eny - - -

(4-acetylpiperazin-l-yl) azetidin-1-yl] butyl } -N-methyl-5- (trif luoromethyl ) 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 fumarate 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 (NK₂) and neurokinin 3 (NK₃) 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 CYP3A4 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 NK₂ 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 three crystal forms of 3-bromo-Λ/-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide fumarate: original sample (bottom), methanol solvate (middle) and dried methanol solvate crystal form (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 fumarate can exist in several forms.

One aspect of the present invention is 3-bromo-Λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4- acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -Λ/-methyl-5-(trifluoromethyl)benzamide fumarate anhydrate. The 3-bromo-7V- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- l-yl]butyl}-Λ/-methyl-5-(trifluoromethyl)benzamide fumarate anhydrate 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):

For the relative intensities the following definitions are used:

A further aspect of the present invention is a methanol solvate of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide fumarate. The methanol solvate of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide fumarate 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):

Another aspect of the present invention is a dried methanol solvate of 3-bromo-N-{(25)-2- (4-fiuorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide fumarate. The dried methanol solvate of 3-bromo-N-{(25)-2- (4-fiuorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide fumarate 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 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 fumarate 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 fumarate 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 (Λ/,Λ/-dimethylformamide), TBTU (N,N,N',N'-tQtmmethyl-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 - yllbutyU-Λ/-methyl-5-(trifluoromethyl)benzamide

3 -Bromo-N- [(25)-2-(4-fluorophenyl)-4-oxobutyl] -TV-methyl- 5 -(trifluoromethyl)benzamide (see below; 11.2 g, 25 mmol) was dissolved in methanol (50 mL) together with triethylamine (3.5 mL, 25 mmol). Together with another portion of triethylamine (3.5 mL, 25 mmol) the solution was transferred to a flask containing l-acetyl-4-azetidin-3- ylpiperazine dihydrochloride (see WO 96/05193; 8.4 g, 32.6 mmol). The mixture was stirred at RT for 45 min and then sodium triacetoxyborohydride (8.0 g, 37.6 mmol) was added by instalments during one hour. The reaction mixture was stirred at RT for 45 min. Water (0.45 mL) was added and then most of the solvent was removed by evaporation. The residue was dissolved in toluene (56 mL) and then an aqueous 10% solution of NaOH (55 mL) was added while heating to 40⁰C. The mixture was stirred vigorously at 45⁰C for 5 min. The aqueous layer was separated off and the organic solution was left in the hood overnight. After several attempts to crystalize the product from different solvents the compound was purified by means of silica gel chromatography (ammonia saturated methanol - methylene chloride 1% to 10%). There was obtained 8.3 g (54%) of the title compound as a white foam. ¹U NMR (500 MHz, CDCl₃): 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 NaHCO₃ 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)benzamide. ¹H NMR (500 MHz, CDCl₃): 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/-methyl-5- (trifluoromethyl)benzamide (0.86 g, 1.9 mmol) in acetone (45 mL) were added OsO₄ (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 OfNaHSO₃ (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 NaIO₄ (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. ¹R NMR (500 MHz, CDCl₃): 2.4-4.4 (cm, 8H), 6.8-7.8 (cm, 7H), 9.8 (s, IH); LCMS: m/z 447 (M-I) ⁺.

Fumarate salt of 3-bromo-7V- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 ■ yPazetidin- 1 -yllbutyU -N-methyl-5-(trifluoromethyl)benzamide

3-bromo-/V- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V- methyl-5-(trifluoromethyl)benzamide (see above; 2.4 g, 3.9 mmol) was dissolved in acetone (10 mL). Fumaric acid (0.863g, 7.43 mmol) was added to acetone (100 mL). Careful heating was necessary to completely dissolve the material. The obtained solution was added to the first one. The resultant warm solution was allowed to cool at RT for 2h, then left overnight in a refrigerator (+4°C). The obtained precipitate was filtered off and dried overnight at reduced pressure. There was obtained 2.476 g (79%) of the title compound. ¹R NMR (500 MHz, DMSO-de): 1.5-1.9 (cm, 2H), 2.0 (s, 3H), 2.2-3.8 (cm, 21H), 6.6 (s, 4H), 7.0-8.0 (cm, 7H).

The fumarate salt was produced as a partially crystalline white powder. The material is an anhydrate with a very slight weight loss (-0.4%) during heating to below the melting point. Above the melting point, the material decomposes. The material is slightly hygroscopic with a water uptake of 1.3% from 0 to 80% relative humidity (RH).

The 3-bromo-7V- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 - yl]butyl}-Λ/-methyl-5-(trifluoromethyl)benzamide fumarate anhydrate 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 fumarate anhydrate, 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. Slurry of 3-bromo-iV- {(26^f)-2-(4-fluorophenyl)-4-r3-(4-acetylpiperazin- 1 -vDazetidin- 1 - yllbutvU-Λ/-methyl-5-(trifluoromethyl)benzamide fumarate (methanol solvate)

About 40 mg of 3-bromo-N-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin-l- yl)azetidin-l-yl]butyl}-Λ/-methyl-5-(trifluoromethyl)benzamide fumarate was suspended in about 500 μl of methanol.

Suspension crystallization was carried out at room temperature in methanol and the product was analyzed with XRPD after two weeks. The slurry in methanol produced a sample with a different crystal form than the starting material, a methanol solvate. By the use of hot-stage XRPD, it is observed that the material obtained after the solvent vaporization is of different crystal form than that of the orginal material.

The methanol solvate of 3-bromo-Λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin-l- yl)azetidin-l-yl]butyl}-Λ/-methyl-5-(trifluoromethyl)benzamide fumarate 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 methanol solvate of 3-bromo-N-{(25)-2-(4- fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide fumarate, shown in the middle 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.

A further form has been observed for the fumarate salt, obtained by drying a methanol solvate at 70⁰C for 6 h ("dried methanol solvate"). The two new crystal forms connected to the suspension in methanol are both of higher crystallinity than the original form.

The dried methanol solvate of 3-bromo-Λ/-{(25)-2-(4-fluorophenyl)-4-[3-(4- acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -Λ/-methyl-5-(trifluoromethyl)benzamide fumarate 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 dried methanol solvate of 3-bromo-N-{(25)-2- (4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -7V-methyl-5- (trifluoromethyl)benzamide fumarate, shown in the top of Figure 1. The relative intensities are less reliable and instead of numerical values the following definitions are used:

Thus, three different crystal forms are known of 3-bromo-Λ/-{(25)-2-(4-fluorophenyl)-4-[3- (4-acetylpiperazin- 1 -yl)azetidin- 1 -yljbutyl} -Λ/-methyl-5-(trifluoromethyl)benzamide fumarate. The X-ray powder diffractograms of all three crystal forms found for 3-bromo- N- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 -yl)azetidin- 1 -yl]butyl} -7V-methyl-5- (trifluoromethyl)benzamide fumarate are displayed in Figure 1.

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.

Claims

1. A fumarate salt of 3-bromo-7V- {(25)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin- 1 - yl)azetidin- 1 -yljbutyl} -Λ/-methyl-5-(trifluoromethyl)benzamide.

2. A fumarate salt according to claim 1 which is an anhydrate.

3. A fumarate salt according to claim 2, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following main peaks with d-values:

4. A fumarate salt according to claims 3, characterized in providing an X-ray powder diffraction pattern essentially as shown in the bottom of Figure 1.

5. A fumarate salt according to claim 1 which is a methanol solvate.

6. A fumarate salt according to claim 5, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following main peaks with d-values:

7. A fumarate salt according to claims 6, characterized in providing an X-ray powder diffraction pattern essentially as shown in the middle of Figure 1.

8. A fumarate salt according to claim 1 which is a dried or partly dried methanol solvate.

9. A fumarate salt according to claim 8, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following main peaks with d-values:

10. A fumarate salt according to claims 9, characterized in providing an X-ray powder diffraction pattern essentially as shown in the top of Figure 1.

11. A fumarate salt as defined in any one of claims 1-10 for use in therapy.

12. A pharmaceutical formulation comprising the fumarate salt according to any one of claims 1-10 in admixture with at least one pharmaceutically acceptable excipient.

13. Use of a compound according to any one of claims 1-10 as active ingredient in the manufacture of a medicament for the prevention or treatment of asthma, allergic rhinitis, pulmonary, 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, gastrointestinal hypermotility, gastric asthma, Crohn's disease, gastric emptying disorders, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease, emesis, gastric motility disorders, functional dyspepsia or gastro-esophageal reflux disease (GERD).

14. Method of treatment or prevention of asthma, allergic rhinitis, pulmonary, 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, gastrointestinal hypermotility, gastric asthma, Crohn's disease, gastric emptying disorders, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease, emesis, gastric motility disorders, functional dyspepsia or gastro-esophageal reflux disease (GERD) which comprises administration of a therapeutically effective amount of a compound according to any one of claims 1-

10, to a patient suffering therefrom.