Patent Application
20110288174
The invention relates to novel forms of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid, in particular to the monohydrate A, to processes for their preparation, to medicaments comprising them and to their use for fighting 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 the formula (I):
Preparation and use of the compound of the formula (I) for treating, for example, cardiovascular disorders are already known from WO 01/019780. Using the procedure described therein, the compound of the formula (I) is obtained in the form of a crystal modification which is referred to as modification IV hereinbelow. Modification IV has a melting point of 129° C. and a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and 13C solid state NMR spectrum (Tab. 1-7,
It has now been found that modification IV is metastable and thus not suitable for use in pharmaceutical formulations such as, for example, solid and semi-solid preparations.
Surprisingly, four further polymorphic forms and the amorphous form have been found. Compared to modification IV, known from WO 01/019780, the polymorphic forms have markedly different melting points 170° C. (modification I), 142° C. (modification II), 135° C. (modification III) and 99° C. (modification V), and each of these modifications has a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and 13C solid state NMR spectrum (Tab. 1-7).
Furthermore, surprisingly, we have found two polymorphic monohydrates A and B, a semihydrate, a methanol solvate and a methanol/water solvate of the compound of the formula (I). The monohydrates each contain a molecule of water, the semihydrate contains ½ molecule of water and the methanol solvate contains 1 molecule of methanol per compound of the formula (I). The methanol/water solvate is a mixed form of the isomorphic semihydrate and the methanol solvate. Each of the two polymorphic monohydrates A and B, the semihydrate, the methanol solvate and the methanol/water solvate of the compound of the formula (I) has a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and 13C solid state NMR spectrum (Tab. 1-7,
The present invention provides the monohydrate of the compound of the formula (I) corresponding to the compound of the formula (II)
in form A.
Surprisingly, the compound of the formula (II) in form A (monohydrate A) is thermodynamically stable and storage-stable even after processing to aqueous suspensions. This increases the safety for preparations comprising the compound of the formula (I), and patient risk is reduced.
In the pharmaceutical formulations, the compound of the formula (II) in form A according to the invention is employed in high purity. For reasons of stability, a pharmaceutical formulation comprises mainly the compound of the formula (II) in form A and no major amounts of any other form of the compound of the formula (I). Preferably, the medicament comprises more than 90 percent by weight, particularly preferably more than 95 percent by weight, of the compound of the formula (II) in the form A based on the total amount of the compound of the formula (I) present.
The present invention furthermore provides the use of the compound of the formula (II) in form A for preparing a medicament for treating diseases, in particular for treating cardiovascular disorders.
The compound of the formula (II) in form A brings about vasorelaxation and an inhibition of platelet aggregation and leads to a lowering of blood pressure and an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylae cyclase and an intracellular increase in cGMP.
It can therefore be employed in medicaments for the treatment of cardiovascular disorders such as, for example, for the treatment of high blood pressure and heart failure, stable and unstable Angina pectoris, peripheral and cardiac vascular disorders, of arrhythmias, for the treatment of thromboembolic disorders and ischemias such as myocardial infarction, stroke, transistory and ischemic attacks, disturbances of peripheral blood flow, prevention of restenoses such as after thrombolysis therapies, percutaneous transluminal angioplasties (PTAs), percutaneous transluminal coronary angioplasties (PTCAs), bypass and for the treatment of arteriosclerosis, fibrotic disorders, such as fibrosis of the liver or pulmonary fibrosis, asthmatic disorders and diseases of the urogenital systems such as, for example, prostate hypertrophy, erectile dysfunction, female sexual dysfunction and incontinence and also for the treatment of glaucoma.
It can also be used for fighting diseases of the central nervous system characterized by disturbances of the NO/cGMP system. It is suitable in particular for removing cognitive deficits, for improving learning and memory performances and for treating Alzheimer's disease. It is also suitable for treating disorders of the central nervous system such as states of anxiety, tension and depression, CNS-related sexual dysfunctions and sleep disturbances, and for controlling pathological disturbances of the intake of food, stimulants and addictive substances.
It is furthermore also suitable for regulating cerebral blood flow and thus represents an effective agent for controlling migraine.
It is also suitable for the prophylaxis and control of the sequelae of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemias and cranial cerebral trauma. It can likewise be employed for controlling states of pain.
In addition, it has an anti-inflammatory effect and can therefore be employed as anti-inflammatory agents.
The present invention furthermore provides a method for treating disorders, in particular the disorders mentioned above, using an effective amount of the compound of the formula (II) in form A.
The compound of the formula (II) in form A can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically, vaginally, as stents or as an implant.
For these administration routes, the compound according to the invention can be administered in suitable administration forms.
Suitable for oral administration are administration forms working according to the prior art, which release the compound of the formula (II) in form A rapidly and/or in modified form, such as, for example, tablets (non-coated or coated tablets, for example coated with enteric, slowly dissolving or insoluble coats which control the release of the compound according to the invention), tablets which decompose rapidly in the oral cavity or films/wafers, films/lyophylisates, capsules (for example hard gelatin capsules or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, suspensions or aerosols.
Parenteral administration can take place with circumvention of an absorption step (for example intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with involvement of an absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration, suitable administration forms are, inter alia, injection and infusion preparations in the form of suspensions, lyophilizates or sterile powders.
Suitable for the other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), tablets, films/wafers or capsules to be applied lingually, sublingually or buccally, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake lotions), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), pastes, dusting powders, implants or stents.
The compound according to the invention can be converted into the administration forms mentioned. This may take place in a manner known per se by mixing with inert non-toxic, pharmaceutically acceptable auxiliaries. These auxiliaries include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colors (e.g. inorganic pigments such as, for example, iron oxides) and taste and/or odor corrigents.
The present invention furthermore provides medicaments comprising at least the compound of the formula (II) in form A, usually together with one or more inert non-toxic, pharmaceutically suitable auxiliaries such as, for example, binders, fillers, etc., and their use for the purposes mentioned above.
In general, it has been found to be advantageous to administer the compound according to the invention in total amounts of from about 0.5 to about 500, preferably from 5 to 100, mg/kg of body weight per day, if appropriate in the form of a plurality of individual doses, to obtain the desired results. An individual dose contains the active compound in amounts of from about 1 to about 80, preferably 3 to 30, mg/kg of body weight.
The invention furthermore provides a process for preparing the compound of the formula (II) in form A, by suspending the compound of the formula (I), for example in modification IV, in an aqueous solvent, preferably ethanol/water (1:1), and stirring or shaking until the desired degree of conversion into monohydrate A has been achieved. The resulting crystals are isolated and dried. The compound of the formula (II) in form A is thus obtained. The method is preferably carried out at a temperature of from 15° C. to 80° C., particularly preferably at from 20 to 30° C.
In general, the preparation processes are carried out under atmospheric pressure. However, it is also possible to operate under elevated or reduced pressure, for example at from 0.5 to 5 bar.
The percentages in the tests and examples below are, unless indicated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentrations of liquid/liquid solutions are in each case by volume.
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 recorded in a Stoe transmission diffractometer. The IR, FIR, NIR and Raman spectra were recorded using Fourier-IR Spectrometers IFS 66v (IR, FIR), IFS 28/N (NIR) and RFS 100 (Raman) from Bruker. The 13C solid state NMR spectra were recorded on a Bruker DRX 400.
About 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. The residue is examined by thermoanalysis and corresponds to the title compound in modification I.
About 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are suspended in 5 ml of acetonitrile and stirred under reflux at 50° C. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. The residue is examined by X-ray diffractometry and corresponds to the title compound in modification I.
About 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are dissolved in about 200 ml of hot ethanol and filtered. One fourth 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 modification I.
About 0.3 g of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are suspended in 5 ml of isopropanol and stirred under reflux at 80° C. After 4 days, the suspension is filtered and the residue is dried at room temperature at ambient humidity. The residue is examined by X-ray diffractometry and corresponds to the title compound as modification I.
About 1 g of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are suspended 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. The residue is examined by X-ray diffractometry and corresponds to the title compound monohydrate A.
About 80 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 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. The residue is examined by thermoanalysis and corresponds to the title compound monohydrate A.
About 0.4 g of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are suspended in 5 ml of ethanol:water (1:1) and stirred under reflux at 50° C. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. The residue is examined by X-ray diffractometry and corresponds to the title compound monohydrate A.
About 80 mg of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are suspended in 1.5 ml of 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. The residue is examined by thermoanalysis and corresponds to the title compound monohydrate A.
About 0.3 g of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are suspended in 5 ml of ethanol:water (1:1) and stirred under reflux at 80° C. After 4 days, the suspension is filtered and the residue is dried at room temperature at ambient humidity. The residue is examined by X-ray diffractometry and corresponds to the title compound monohydrate A.
About 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 about 200 ml of hot acetone and filtered. One fourth 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 monohydrate B.
About 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 about 200 ml of hot isopropanol and filtered. Water is added to one fourth of the solution until the active compound precipitates. The precipitated active compound is isolated and dried at room temperature at ambient humidity. The active compound is examined by thermoanalysis and corresponds to the title compound monohydrate B.
About 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 about 200 ml of hot acetone and filtered. One fourth of the solution is allowed to stand at 5 to 8° C. until the solvent has evaporated. The residue is examined by thermoanalysis and corresponds to the title compound monohydrate B.
About 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 about 200 ml of hot acetonitrile and filtered. Water is added to one fourth of the solution until the active compound precipitates. The precipitated active compound is isolated and dried at room temperature at ambient humidity. The active compound is examined by X-ray diffractometry and corresponds to the title compound monohydrate B.
About 100 mg of the monohydrate of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in form A are tempered at 70° C. in a drying cabinet for 10 min. The active compound is examined by X-ray diffractometry and corresponds to the title compound in modification II.
About 100 mg of the monohydrate of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in form A are tempered at 100° C. in a drying cabinet for 5 min. The active compound is examined by thermoanalysis and corresponds to the title compound in modification II.
About 100 mg of the monohydrate of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in form A are stored over phosphorus pentoxide at room temperature for 2 days. The active compound is examined by thermoanalysis and corresponds to the title compound in modification II.
About 0.4 g of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification II are dissolved in about 200 ml of hot methanol and filtered. One fourth of the solution is allowed to stand at about −20° C. until the solvent has evaporated. The crystal structure of the residue is determined. The residue corresponds to the title compound as semihydrate.
4 g of 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 1.5 l of hot methanol and filtered. The solutions are divided into five parts, allowed to stand at room temperature until the solvent has evaporated and combined to one sample. The crystal structure of the residue is determined. The residue corresponds to the title compound as methanol solvate.
About 0.6 g of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are dissolved in about 500 ml of hot methanol 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.
2-3 mg of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are heated in a DSC calorimeter. From the melt of modification IV, modification III crystallizes on further heating.
About 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 tempered at 70° C. in a drying cabinet for 3 h. The active compound is examined by thermoanalysis and corresponds to the title compound in modification V.
About 70 mg of the methanol/water solvate of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid are stored over phosphorus pentoxide at room temperature for 2 days. The active compound is examined by X-ray diffractometry and corresponds to the title compound in modification V.
About 80 mg of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are melted on a Kofler hot stage and rapidly cooled to room temperature. The active compound is examined by X-ray diffractometry and corresponds to the title compound in amorphous form.
About 100 mg of 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid in modification IV are melted at 180° C. in a drying cabinet for 10 min and rapidly cooled to room temperature. The active compound is examined by X-ray diffractometry and corresponds to the title compound in amorphous form.
13C Solid state NMR spectroscopy
| Number | Date | Country | Kind |
|---|---|---|---|
| 102008062688.0 | Dec 2008 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP09/08739 | 12/8/2009 | WO | 00 | 8/11/2011 |
