EP2379489A1

EP2379489A1 - Modification i of 4-({4-carboxybutyl)ý2-(2-{ý4-(2-phenylethyl)benzyl¨oxy}phenyl)ethyl¨-amino}methyl)benzoic acid

Info

Publication number: EP2379489A1
Application number: EP09774834A
Authority: EP
Inventors: Alfons Grunenberg; Franz-Josef Mais; Katharina Tenbieg; Birgit Keil
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2008-12-17
Filing date: 2009-12-04
Publication date: 2011-10-26
Also published as: WO2010075930A1; US20120010292A1; TW201034661A; AR075489A1; CA2746870A1; JP2012512204A; DE102008062689A1

Abstract

The invention relates to novel forms of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid, especially modification I, methods for the production thereof, medicaments containing the same, and the use thereof for fighting diseases.

Description

Modification I of 4 - ({(4-carboxybutylM2- (2 - ([4-f2-phenylethvbenzylloxy} phenyl) ethyleneaminol methvobenzoic acid

The invention relates to novel forms of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid, especially the modification I, process for their preparation, medicaments containing them and their use in the control of diseases.

4 - ({(4-Carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid is described in WO 01/019780 and corresponds to the compound of Formula (I):

The preparation and use of the compound of the formula (I) for the treatment of, for example, cardiovascular diseases is already known from WO 01/019780. In the manner described there, the compound of the formula (I) is obtained in the form of a crystal modification, which is referred to below as modification IV. Modification IV has a melting point of 129 ° C and a characteristic X-ray diffraction pattern, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and ¹³ C solid-state NMR spectrum (Tab. 1-7, Fig. 1-7) ,

It has now been found that modification IV is metastable and therefore not suitable for use in pharmaceutical formulations such as solid and semi-solid preparations.

Surprisingly, four more polymorphic forms and the amorphous form were found. The polymorphic forms have in comparison to the WO 01/019780 known modification IV significantly different melting points of 170 ⁰ C (modification I), 142 ° C (modification II), 135 ° C (modification EI) and 99 ° C (modification V) and each have a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and ¹³ C Festköφer NMR spectrum (Tab. 1-7, Fig. 1-7). Figure 8 additionally shows the crystal structure of the compound of the formula (I) in the modification I.

Furthermore, surprisingly, two polymorphic monohydrates A and B, a semihydrate, a methanol solvate and a methanol-water solvate of the compound of formula (T) were found. The monohydrates each contain one molecule of water, the semihydrate contains ¹ A. Molecule of water and the methanol solvate contains 1 molecule of methanol per compound of formula (J). The methanol-water solvate is a mixed form of the isomorphic semihydrate and the methanol solvate. The two polymorphic monohydrates A and B, the semihydrate, the methanol solvate and the methanol-water solvate of the compound of the formula (I) each have a characteristic X-ray difogram, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and ¹³ C solid-state NMR spectrum (Tables 1-7). From the semi-hydrate and the methanol solvate, a crystal structure clarification was performed (Table 8).

The present invention relates to the compound of the formula (I) in the modification I.

Surprisingly, the modification I of the compound of formula (I) is thermodynamically stable and stable even after processing via suspensions. The use according to the invention of the compound of the formula (I) in the stable modification I ensures that an undesired conversion into another modification and a concomitant change in the properties of the compound of the formula (I), for example solubility or

Bioavailability be avoided. This increases the safety and quality of preparations containing the compound of formula (I) and reduces the risk to the patient.

The compound of the formula (I) according to the invention in the modification I is used in high purity in pharmaceutical formulations. For stability reasons, a pharmaceutical formulation mainly contains the compound of the formula (I) in the modification I and no major proportions of any other form of the compound of the formula (I). The medicament preferably contains more than 90% by weight, particularly preferably more than 95% by weight of the compound of the formula (I) in the modification I based on the total amount of the compound of the formula (I).

Another object of the present invention is the use of the compound of formula (I) in the modification I for the manufacture of a medicament for the treatment of diseases, in particular for the treatment of cardiovascular diseases.

The compound of formula (I) in the modification I leads to a vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure and to an increase of the coronary Blood flow. These effects are mediated via direct stimulation of soluble guanylate cyclase and intracellular cGMP increase.

It can therefore be used in medicaments for the treatment of cardiovascular diseases such as hypertension and cardiac insufficiency, stable and unstable angina pectoris, peripheral and cardiovascular diseases, arrhythmias, for the treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transient and ischemic attacks , peripheral circulatory disorders, prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass and for the treatment of arteriosclerosis, fibrotic diseases such as liver fibrosis or pulmonary fibrosis, asthmatic diseases and diseases of the genitourinary system such as prostatic hypertrophy, erectile Dysfunction, female sexual dysfunction and incontinence, as well as for the treatment of glaucoma.

It can also be used to control central nervous system diseases characterized by NO / cGMP system disorders. In particular, it is suitable for

Eliminate cognitive deficits, improve learning and memory performance, and

Treatment of Alzheimer's disease. It is also suitable for the treatment of central nervous system disorders such as states of anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders of food, pleasure and addiction.

Furthermore, it is also suitable for the regulation of cerebral blood flow and thus represents an effective means of combating migraine.

It is also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma. It can also be used to combat pain.

In addition, it has anti-inflammatory action and can therefore be used as an anti-inflammatory agent.

Another object of the present invention is a method for the treatment of diseases, in particular the aforementioned diseases, using an effective amount of the compound of formula (I) in the modification I. The compound of the formula (I) in the modification I can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically, vaginally or as an implant or stent.

For these administration routes, the compound according to the invention can be administered in suitable administration forms.

For oral administration, the prior art is capable of rapidly and / or modifying the compound of formula (T) in the modification I-donating administration forms, e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, suspensions or aerosols.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of suspensions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), pastes, scattering powders, implants or stents.

The compounds according to the invention can be converted into the stated forms of application.

This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Carriers (for example, microcrystalline cellulose, lactose, mannitol). Solvent (e.g., liquid polyethylene glycols).

Emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate,

Polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural

Polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides), and

Flavor and / or odor remedies. Another object of the present invention are pharmaceutical compositions containing at least the compound of formula (I) in the modification I, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients such as binders, fillers, etc., as well as their use in the previously mentioned purposes.

In general, it has proved to be advantageous to administer the compound of the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per day, optionally in the form of several single doses to achieve the desired results. A single dose contains the active ingredient in amounts of about 1 to about 80, preferably 3 to 30 mg / kg of body weight.

The invention further provides a process for the preparation of the compound of the formula (I) in the modification I, by suspending the compound of the formula (I), for example in the modification IV, in an inert solvent and, until the desired degree of conversion is achieved, being particularly preferred until the quantitative conversion to the modification I at a temperature of 10 ⁰ C to the reflux temperature of the solvent, preferably at 15 ° C to 35 ° C, more preferably stirred at 20 to 30 ⁰ C or shakes. The resulting crystals of modification I are separated and dried to constant weight at room temperature or at elevated temperature to remove the solvent present.

Also, the compound of the formula (I) in the modification I can be prepared by, for example, dissolving the compound of the formula (I) in the modification IV in an inert solvent and allowing it to stand at room temperature until the solvent has evaporated.

Preferably, the preparation of the compound of formula (I) in the modification I, by dissolving the compound of formula (I) in the modification IV in ethanol and the solution is allowed to stand at room temperature until the compound of formula (T) in the Modification I crystallized.

Suitable inert solvents are lower alcohols, such as methanol, ethanol, n-propanol, isopropanol. n-butanol. sec-butanol. iso-butanol. 1-Pentanoi or ketones such as acetone, or alkanes such as n-pentane, cyclopentane, n-hexane, cyclohexane, or tetrahydrofuran, acetonitrile, toluene, ethyl acetate, 1,4-dioxane or mixtures of said solvents. Preference is given to acetonitrile, isopropanol, ethanol or mixtures of the solvents mentioned.

Generally, the manufacturing processes are carried out under atmospheric pressure. However, it is also possible to work at an elevated or reduced pressure, for example from 0.5 to 5 bar. The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

Exemplary embodiments:

The DSC and TGA thermograms were obtained using a differential scanning calorimeter DSC 7 or Pyris-1 and a Thermogravimetric Analyzer TGA 7 from Perkin-Elmer. The X-ray diffractograms were registered in a Stoe transmission diffractometer. The IR, FIR, NIR and Raman spectra were recorded with Fourier IR spectrometers IFS 66v (IR, FIR), IFS 28 / N (NIR) and RFS 100 (Raman) from Bruker. The ¹³ C solid-state NMR spectra were recorded with a Bruker DRX 400.

example 1

Preparation of 4- (f (4-carboxybutyl ^') ^|' 2- (2- (r4- ( ^{'2-phenylethyl)} ^benzyl' | oxy) phenyl) ethyl] amino> - methvDbenzoesäure in the modification I

Example 1.1

Approximately 100 mg of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} -methyl) benzoic acid in modification IV are suspended in 1 ml of ethyl acetate and shaken at 25 ° C. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is investigated thermoanalytically and corresponds to the title compound in the modification I.

Example 1.2

Approximately 0.4 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} -methyl) benzoic acid in modification IV are dissolved in 5 ml Suspended acetonitrile and stirred at 50 ⁰ C at reflux. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound in the modification I.

Example 1.3

Approximately 400 mg of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} - methyl) benzoic acid in the modification IV are dissolved in about 200 ml Dissolved hot ethanol and filtered. One quarter of the solution is allowed to stand at room temperature until the solvent has evaporated. The residue is examined by X-ray diffractometry and corresponds to the title compound in the modification I.

Example 1.4

Approximately 0.3 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} -methyl) benzoic acid in the modification IV are dissolved in 5 ml Isopropanol suspended and stirred at 80 ⁰ C at reflux. After 4 days, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound as modification I.

Example 2

A preparation of the monohydrate of 4 - ({(4-carboxybutyl ^") ^*) benzylloxyl- phenyl) ethyl] amino r2- (2- {J4 (2-phenylethyl) methyl) benzoic acid

Example 2.1

Approximately 1 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in modification IV are dissolved in 40 ml of ethanol: Water (1: 1) and stirred at room temperature. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound as monohydrate A.

Example 2.2

Approximately 80 mg of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} -methyl) benzoic acid in the modification IV are dissolved in 1 ml of tetrahydrofuran: Water (1: 3) and shaken at 25 ° C. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is investigated thermoanalytically and corresponds to the title compound as monohydrate A.

Example 2.3

Approximately 0.4 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in 5 ml Ethanol: water (1: 1) and stirred at 50 ⁰ C at reflux. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound as monohydrate A. Example 2.4

Approximately 80 mg of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} -methyl) benzoic acid in the modification IV are dissolved in 1.5 ml Isopropanol: water (2: 1) and shaken at 25 ° C. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is investigated thermoanalytically and corresponds to the title compound as monohydrate A.

Example 2.5

Approximately 0.3 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in 5 ml Ethanol: water (1: 1) and stirred at 80 ⁰ C at reflux. After 4 days, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound as monohydrate A.

Example 3

Benzoic acid methyr) Preparation of Monohvdrats B of 4 - (phenyl) ethyl] ammo ((4-carboxybutyl ^') r2- (2 - - {[4- (2-phenylethyl) benzyl] oxy))

Example 3.1

Approximately 0.4 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in ca. Dissolve 200 ml of acetone while hot and filter. One quarter of the solution is allowed to stand at room temperature until the solvent has evaporated. The residue is examined by X-ray diffractometry and corresponds to the title compound as monohydrate B.

Example 3.2

Approximately 0.4 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in ca. 200 ml of isopropanol dissolved hot and filtered. One quarter of the solution is mixed with water until the drug precipitates. The precipitated active ingredient is isolated and dried at room temperature at ambient humidity. It is investigated thermoanalytically and corresponds to the title compound as monohydrate B.

Example 3.3 Approximately 0.4 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in ca. Dissolve 200 ml of acetone while hot and filter. One quarter of the solution is allowed to stand at 5 to 8 ° C until the solvent has evaporated. The residue is investigated thermoanalytically and corresponds to the title compound as monohydrate B.

Example 3.4

Approximately 0.4 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in ca. Dissolved 200 ml acetonitrile hot and filtered. One quarter of the solution is mixed with water until the drug precipitates. The precipitated active ingredient is isolated and dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound as monohydrate B.

Example 4

Preparation of 4- (((4-carboxybutyl ^") r2-f 2- ^(|" 4- (2-phenylethyl) benzylloxy) phenyl) ethyl1amino} - methvDbenzoesäure in the modification π

Example 4.1

Approximately 100 mg monohydrate A of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid are at 70 ⁰ for 10 min C tempered in a drying oven. The active ingredient is examined by X-ray diffractometry and corresponds to the title compound in the modification II.

Example 4.2

Approximately 100 mg of monohydrate A of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid are at 100 ⁰ for 5 min C tempered in a drying oven. The active ingredient is investigated thermoanalytically and corresponds to the title compound in the modification IL

Example 4.3

Approximately 100 mg of monohydrate A of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid are passed through phosphorus pentoxide at room temperature for 2 days stored. The active ingredient is investigated thermoanalytically and corresponds to the title compound in the modification II. Example 5

Preparation of the semihvate of 4 - ({(4-carboxybutyl) [2- (2- {r4- (2-phenylethvbenzyl) oxy} -phenydimethylaminopropylbenzoic acid

Example 5.1

Approximately 0.4 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification II are dissolved in approx. 200 ml of methanol dissolved hot and filtered. One quarter of the solution is left at about -20 ⁰ C until the solvent has evaporated. The residue is subjected to a crystal structure anneal. It corresponds to the title compound as a semihydrate.

Example 6

Preparation of the methanol solvate of 4 - ({(4-carboxybutyryl- (2 - {[4- (2-phenylethyl) benzyl] oxy> -phenyl ^" ) ethyl] aminolmethyl) benzoic acid

Example 6.1

4 _{g of} 4- ({(4-carboxybutyl) [2- (2- {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in 1.5 l Dissolved methanol hot and filtered. The solutions are filtered, allowed to stand at room temperature until the solvent has evaporated and combined to a sample. From the residue, a crystal structure determination is performed. It corresponds to the title compound as a methanol solvate.

Example 7

Preparation of the methanol-water solvate of 4 - ({(4-carboxybutyl) | ^"2- (2 - [benzyl 4- (2-phenylethylV] {oxy} phenyl) ethyl] aminolmethyl) benzoic acid

Example 7.1

Approximately 0.6 g of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in ca. 500 ml of methanol dissolved hot and filtered. The solution is allowed to stand at room temperature until the solvent has evaporated. The residue is examined by X-ray diffractometry and corresponds to the title compound as methanol-water solvate. Example 8

Preparation of 4 - (((4-carboxybutyl ^') r2- (2 - ([4- ^{(2-phenylethyl')} benzyl1oxy> phenyl ^') ethyllamino) - methvDbenzoesäure in the modification in

Example 8.1

2-3 mg of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid in the modification IV are dissolved in the DSC Calorimeter heated up. From the melt of the modification FV crystallizes during further heating, the modification HI.

Example 9

Preparation of 4 - (((4-carboxybutyl ^') r2- (2- (r4- ^{(2-phenylethyl')} benzyl1oxy} phenyl ^') ethyl] amino> - methvDbenzoesäure in the modification V

Example 9.1

Approximately 100 mg of the methanol-water solvate of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid are added 3 h annealed at 70 ⁰ C in a drying oven. The active ingredient is investigated thermoanalytically and corresponds to the title compound in the modification V.

Example 9.2

Approximately 70 mg of the methanol-water solvate of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) benzoic acid become 2 days stored over phosphorus pentoxide at room temperature. The active ingredient is examined by X-ray diffractometry and corresponds to the title compound in the modification V.

Example 10

Preparation of the amorphous form of 4 - ({(4-carboxybutyl) [2- (2- {r4- (2-phenylethyl ^') - benzyl1oxy} phenyl) ethyl] amino} methyl) benzoic acid

Example 10.1

Approximately 80 mg of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} - methyl) benzoic acid in the modification IV are used on the Kofier heating bench melted and cooled quickly to room temperature. The active substance is examined by X-ray diffractometry and corresponds to the title compound in amorphous form. Example 10.2

Approximately 100 mg of 4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} - methyl) benzoic acid in the modification IV 10 min at 180 ⁰ C melted in the oven and quickly cooled to room temperature. The active substance is examined by X-ray diffractometry and corresponds to the title compound in amorphous form.

Tab. 1: Differential scanning calorimetry and thermogravimetry

Tab. 2: X-ray diffractometry

Tab. 3: IR spectroscopy

Tab. 4: Raman spectroscopy

Tab. 5: FIR spectroscopy

Tab. 6: NIR spectroscopy

Tab. 7: ¹³ C solid-state NMR spectroscopy

Tab. 8: Crystal structure data

Claims

claims:

1. Compound of formula (I)

in modification I.

2. A compound according to claim 1, characterized in that the Röntgendifrraktogramm of the compound shows a peak maximum of the 2 theta angle at 9.6.

3. A compound according to claim 1, characterized in that the X-ray diffraction pattern of the compound shows peaks of the 2 theta angle at 9.6, 15.8 and 24.7.

4. A compound according to claim 1, characterized in that the Raman spectrum of the compound shows a band at 2930 cm ^-1 .

5. A compound according to claim 1, characterized in that the Raman spectrum of the compound bands at 2930, 1616 and 1602 cm ^"1 shows.

6. A compound according to claim 1, characterized in that the NIR spectrum of the compound bands at 5974, 4613 and 4053 cm ^"1 shows.

7. A compound according to any one of claims 1 to 6 for the treatment of diseases.

8. A medicament comprising a compound according to any one of claims 1 to 6 and no major proportions of another form of the compound of formula (I).

9. A medicament comprising a compound according to any one of claims 1 to 6 in more than 90 percent by weight based on the total amount of the compound of formula (I).

10. A process for the preparation of the compound according to any one of claims 1 to 6, by suspending the compound of formula (I) in the modification IV in an inert solvent and until the quantitative conversion to the modification I at a temperature of 10 ° C to The reflux temperature of the solvent is stirred or shaken.

11. Use of the compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of cardiovascular diseases.

12. A method for the treatment of cardiovascular diseases by administering an effective amount of a compound according to any one of claims 1 to 6.