A process for the preparation of a compound and its purification for use as an active pharmaceutical ingredient

Abstract

The present invention relates to a process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) and to the preparation and use of crystalline modification I of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I).

Description

[0001] This application is a divisional application of the patent application for invention entitled "Process for the preparation of a compound and its purification for use as an active pharmaceutical ingredient" with the number 201580053456.7. The original application corresponds to the international application PCT / EP2015 / 067340, filed on 29 July 2015, with a priority date of 1 August 2014. TECHNICAL FIELD

[0002] The present invention relates to a novel, improved process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- naphthyridine-3-carboxamide of formula (I),

[0003]

[0004] and the preparation and use of crystalline polymorph I of (4S)-4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxamide of formula (I). BACKGROUND

[0005] The compound of formula (I) acts as a non-steroidal antagonist of the mineralocorticoid receptor and can be used as a medicament for the prevention and / or treatment of cardiovascular and renal disorders such as heart failure and diabetic nephropathy.

[0006] The compound of formula (I) and its preparation are described in WO 2008 / 104306 and in ChemMedChem 2012, 7, 1385, wherein both publications disclose a detailed discussion of the synthesis studies. The disadvantage of the synthesis methods described therein lies in the fact that the synthesis methods are not suitable for further large-scale processes, since many steps are carried out with highly excessive amounts of reagents at very high dilution, resulting in a relatively low overall yield. Furthermore, chromatographic purification processes of many intermediates are necessary, which are usually very technically cumbersome and require the consumption of large amounts of solvents, which are expensive and should therefore be avoided as far as possible. Some stages are difficult to realize due to safety and process technical difficulties.

[0007] Therefore, there is a need for an industrially feasible synthesis method which provides the compound of formula (I) in a reproducible manner with a high overall yield, low production costs and high purity and which meets all regulatory requirements in order to provide clinical trials of the active ingredient and for later regulatory submissions.

[0008] According to the present invention, a very effective synthesis method has been found which meets the above requirements.

[0009] In the publication ChemMedChem 2012, 7, 1385, which discloses a research-scale synthesis of the compound of formula (I), the compound of formula (I) is prepared in 10 stages starting from vanillin with an overall yield of 3.76% of theory. The compound of formula (I) is obtained as amorphous solid by evaporation of the chromatographic fractions; so far no defined crystallization process for the polymorph adjustment of the last stage has been described.

[0010] The following scheme 1 shows a known process for the preparation of the compound of formula (I).

[0011]

[0012]

[0013] Scheme 1 : Research-scale synthesis of the compound of formula (I)

[0014] Three chromatographic purifications as well as one chiral chromatographic stage for the separation of the enantiomers of the racemate of formula (XIII) are used. Some stages are carried out at very high dilution and with very large amounts of reagents.

[0015] For example, the preparation sequence of the nitrile-aldehyde intermediate (VI), which plays a central role in the synthesis, is unacceptable in terms of atom economy.

[0016] Furthermore, the process cannot be transferred to the industrial scale, since firstly very expensive reagents such as triflic anhydride [(III) => (IV)] and an excess of tert-butyl acrylate are used. On scaling up the Heck reaction (IV) => (V), residues in the form of plastics are formed in the tank, which originate from the polymerization of the excess tert-butyl acrylate. Since there is a risk of breakage of the stirrer and of the residues in the stirrer apparatus becoming too hard to remove, this is not acceptable in an industrial process.

[0017] It should also be avoided to subsequently cleave the double bond with sodium periodate and the highly toxic osmium tetroxide, since under the described experimental conditions, a reaction delay occurs, which leads to an exothermic reaction, which can lead to an uncontrolled reaction. SUMMARY

[0018] Scheme 2 shows the new process of the present application, which gives the compound of formula (I) in 9 stages with an overall yield of 27.7% of theory, without chromatographic purification of the intermediates.

[0019]

[0020]

[0021] Scheme 2: Process for the preparation of compounds of formula (I) according to the present application

[0022] Without isolating the methyl ester (XV) and the aldehyde (XVI) but further reacting them directly in solution, only 7 stages need to be isolated. The enantiomeric separation is performed using a preparative chiral HPLC method (e.g. SMB technology, Varicol).

[0023] The aldehyde (VI) is known from the literature (J. Med. Chem. 2007, 50, 2468-2485) and is an important intermediate in this synthesis. Also, the compound is commercially available.

[0024]

[0025] Starting from 4-cyano-2-methoxytoluene (VIa), the dibromide (VIb) is prepared with NBS, which is reacted with 2.46 equivalents of silver nitrate in ethanol in water to give the target aldehyde (VI). This synthesis described in the literature and the method described in the synthesis on a research scale are completely unsuitable for scaling up to a multi-tonnes scale, so that a new, more efficient and economically more viable synthesis is urgently needed.

[0026] The halogenated benzoic acids (XIV) and (XIVa) are commercially available in relatively large amounts.

[0027]

[0028] A very efficient and cheaper process has been developed, in which the intermediates (XV) and (XVI)

[0029]

[0030] but are further reacted dissolved in solution. This is only possible because the yields and the purity of the individual reactions are very high (> 95% of the theoretical value). The methyl ether ester (XV) is known from the literature (Journal of Medicinal Chemistry, 1992, Vol. 35, pp. 734-740) and is prepared by reaction with methyl iodide, which is highly volatile, harmful to health and expensive.

[0031] It was shown by the new process according to the application that it is possible to use analogously non-volatile, less expensive dimethyl sulfate. Starting from the acid (XIV), the reaction of the acid in a solvent, for example acetone, 2-butanone, THF, 2-methyl-THF, DMF, DMA or NMP, with dimethyl sulfate at a temperature of 50-100°C with the aid of a base auxiliary, for example potassium carbonate, sodium carbonate, calcium carbonate, lithium carbonate, N-methylimidazole, triethylamine, pyridine or 2,6-lutidine, gives the methyl ether ester (XV). Here, the methods known to the person skilled in the art for esterification of acids and etherification of phenols (Tetrahedron, 2013, Vol. 69, pp. 2807-2815; Journal of the American Chemical Society, 2013, Vol. 135, pp. 5656-5668) are used. It has been found that the use of dimethyl sulfate and potassium carbonate in acetone at reflux (56°C) is particularly preferred. In this case, the dimethyl sulfate is added to the boiling reaction mixture within 4 hours. The acetone is distilled off and replaced by toluene (distillation again). For the workup, water is added (decomposition of excess dimethyl sulfate), the toluene phase is separated off and washed with water and saturated sodium chloride solution, and then the toluene solution is distilled off to volume (used as azeotropic drying, i.e. removal of water for the subsequent stage). Determination of the solution content shows almost complete conversion (>96% of the theoretical value). Chloro compounds can be used analogously to the bromo compounds, achieving the same conversion.

[0032] The preparation of aldehydes (XVI) is described in the literature, examples include: Glaxo Group Limited US 2008 / 312209 Al, 2008; European Journal of Medicinal Chemistry, 1986, Vol. 21, pp. 397-402; Journal of Medicinal Chemistry, 1992, Vol. 35, pp. 734-740; Journal of Materials Chemistry, 2011, Vol. 21, pp. 9523-9531. However, the starting materials used in the reaction are very expensive and not available in large quantities, so a new process starting from the methyl ether ester (XV) was developed. By adding N-methylpiperazine, (XV) can be converted to the aldehyde (XVI) using REDAL (sodium bis(2-methoxyethoxy)aluminum dihydride) in toluene. This process is described in the literature (Synthesis 2003, Issue 6, 823-828 and Tetrahedron 57 (2001) 2701-2710). If the reaction is carried out stoichiometrically similar to that described in the literature, in addition to the aldehyde described, another compound is found in the mixture. It has been shown that this is the corresponding benzyl alcohol formed by up to 10% over-reduction. It has been shown that it is important to adjust the stoichiometry of REDAL and N-methylpiperazine exactly to 1.21 equivalents of REDAL + 1.28 equivalents of N-methylpiperazine, which makes it possible to reduce this side product, which disrupts the crystallization in the subsequent stage, to <1%. For this purpose, 65% REDAL in toluene is added at 0-5°C (preferably 1.21 equivalents) and 1.28 equivalents of N-methylpiperazine are added. The N-methylpiperazine-containing REDAL solution thus obtained is added to a solution of the bromomethyl ester (XIV) in toluene within about 30 minutes, after which the mixture is stirred at 0°C for 1 hour. The reaction solution is quenched in water / acid (preferably aqueous sulfuric acid), the toluene phase is separated and washed with water and saturated sodium chloride solution. The toluene is distilled off and redistilled in DMF (solvent for the subsequent stage). The reaction yield is usually >94% of the theoretical value. The corresponding reaction with the chloro compound is carried out analogously and the yield is comparable. The DMF solution is used directly in the subsequent reaction.

[0033] In a further synthesis process, the bromo aldehyde (XVI) is converted into a nitrile (Synth. Commun. 1994, 887-890; Angew. Chemie 2003, 1700-1703; Tetrahedron Lett. 2007, 2555-2557; Tetrahedron Lett. 2004, 1441-1444; JACS 2003, 125, 2890-2891; Journal of Organometallic Chemistry 689 (2004), 4576-4583) in a manner known per se by methods familiar to the person skilled in the art, wherein in this case the nitrile aldehyde (VI) is obtained. It has proved to be particularly advantageous in the case of bromo compounds to carry out the palladium-catalysed reaction with potassium hexacyanoferrate * 3 H2O as cyanide source (Tetrahedron Lett. 48 (2007), 1087-1090). For this purpose, the bromo aldehyde (XVI) is added to DMF (8-10 times), 0.22 equivalents of potassium hexacyanoferrate * 3 H2O and 1 equivalent of sodium carbonate are added, followed by 0.005 equivalents of palladium acetate. The mixture is heated to 120°C for 3 hours. The solution is cooled to 20°C, water and ethyl acetate are then added. The ethyl acetate phase is separated off, the aqueous phase is washed again with ethyl acetate, and the combined ethyl acetate phases are then redistilled in isopropanol. The product is precipitated by the water precipitation method at the boiling temperature. After separation, the product is dried in vacuo. In some cases, the product is precipitated directly by the addition of water to the DMF and used directly in the subsequent stage after separation and drying. The reaction yield is generally > 85% of theory. Palladium acetate is not suitable for the conversion of chloro compounds and it has proved to be advantageous in this case to use palladium catalysts familiar to the person skilled in the art (for example as described in Tetrahedron Lett. 48 (2007), 1087-1090), wherein the yield is slightly lower than for bromo compounds, generally 80-85% of theory.

[0034] The cinnamyl esters (VIII a,b) are obtained in the form of an E / Z mixture by Knoevenagel reaction of the aldehyde of the formula (VI) with the cyano ester (VIII) starting from the aldehyde of the formula (VI):

[0035]

[0036] In the process investigated, 16.6 times the amount of dichloromethane and 0.2 equivalents of piperidine / 0.2 equivalents of glacial acetic acid are heated on a water separator for 20 hours. After aqueous work-up, the product is crystallised from methanol after evaporation of the solvent to give the target compound in 52% of theory.

[0037] The reaction is preferably carried out in a water separator on boiling dichloromethane (10-fold) by addition of 5-20 mol% piperidine (preferably 10 mol%) and 5-20 mol% glacial acetic acid (preferably 5-10 mol%). The reaction time is 4-12 h, but preferably 5-6 h, particularly preferably 6 h. 1.0-1.5 equivalents, however preferably 1.1 to 1.35 equivalents or 1.25 equivalents to 1.35 equivalents of the cyano ester (VII) are added. Particularly preferably, 1.1 equivalents are added. The preparation of the cyano ester (VII) is described in Pharmazie, 2000, volume 55, pages 747-750 and Bioorg. Med. Chem. Lett. 16, 798-802 (2006). After completion, the reaction is cooled to 20°C, the organic phase is washed twice with water. The organic washings are redistilled in 2-butanol and the E / Z cinnamate mixture (VIII a+b) is used without intermediate separation directly in the subsequent reaction with the heterocycle (IX) to give the dihydropyridine (X):

[0038]

[0039] For the further reaction in the synthesis on research scale, the mixture is heated with the heterocycle (IX) in isopropanol under reflux for 40 h.

[0040] It has been found that the reaction can be carried out at temperatures of 80-160°C, at atmospheric pressure and in an autoclave (2-10 bar), preferably in a secondary alcohol such as isopropanol, isobutanol, 2-pentanol or cyclohexanol, the reaction time being 8-40 h, but preferably 20-25 h in boiling 2-butanol at atmospheric pressure or in isopropanol in an autoclave (100°C, 2-10 bar, preferably 3-5 bar, 8-24 h). For the work-up, the mixture is cooled to 0°C to 20°C, the crystals are filtered off and washed with isopropanol and then dried (in vacuo, 60°C).

[0041] If, for environmental economic reasons, the use of dichloromethane should be omitted, it has proved advantageous to prepare the cinnamyl esters (VIII a,b) in isopropanol, in which case the aldehyde (VI) is added to isopropanol (3-9 times, preferably 5-7 times) and 5-20 mol% piperidine (preferably 5-10 mol%, 10 mol%) and 5-20 mol% glacial acetic acid (preferably 5-10 mol% or 10 mol%) are added. 1.0-1.5 equivalents, preferably 1.1-1.35 equivalents or 1.35 equivalents, particularly preferably 1.1 equivalents, of the cyano ester (VII) are added at 30°C over 3 hours, optionally dissolved in a small amount of isopropanol, and the mixture is stirred at 30°C for 1 hour. During the reaction, the cinnamyl ester (VIII a,b) crystallizes out. The product is then filtered off, optionally washed with a small amount of isopropanol (cooled to 0°C) after cooling, preferably at 0°C, and used wet in the subsequent reaction as described above. The yield is > 96% of theory. The subsequent reaction is preferably carried out at 100°C under pressure in 10-15 times (relative to the aldehyde (VI)), preferably 11-12 times, isopropanol for 20-24 hours. After the reaction has ended and cooled, the product is separated by filtration or centrifugation. The product is then dried under vacuum at 40-90°C. Since the conversion to the cinnamyl ester is almost quantitative, the process for the subsequent stage can be easily standardized without having to adjust the amount of heterocycle (IX) in each case, since the product can be used wet with isopropanol. The yield is > 87% of theory. The heterocycle (IX) can be prepared by known literature methods, such as the method described in Synthesis 1984, 765-766.

[0042] From the dihydropyridine (X), the ethyl ether (XI) is obtained by reaction with an ortho ester (where R is -H or -methyl) under acidic catalysis:

[0043]

[0044] In the synthesis on research scale, the reaction was carried out at 135°C in 25 times DMF with 20.2 equivalents of triethyl orthoformate and a catalytic amount of concentrated sulfuric acid. The mixture was concentrated to dryness and the residue was purified by chromatography with a yield of 86% of theory. Due to the high dilution and the use of triethyl orthoformate (highly flammable at low temperatures), which is used in a great excess, and the subsequent chromatography, this method is not suitable as a process procedure.

[0045] Surprisingly, it has been found that the reaction can be carried out highly concentrated (up to 1.5 g solvent per 1 g reactants) in solvents such as dimethylacetamide, NMP (1-methyl-2-pyrrolidone) or DMF (dimethylformamide) by adding 4-10% by weight, preferably 6-8% by weight, of concentrated sulfuric acid. Surprisingly, the reaction is even carried out using 2.5-5 equivalents or 5 equivalents of orthoester. It has been found that the use of the corresponding triethyl orthoacetate in the reaction is more convenient because, on the one hand, it makes the reaction cleaner and it is less flammable, and thus particularly suitable for the process sequence. The reaction is preferably carried out in DMA (dimethylacetamide) and / or NMP (1-methyl-2-pyrrolidone) at a temperature of 100-120°C, preferably 115°C. It has proven advantageous to distil off some solvent (DMA and / or NMP) at elevated temperature (100-120°C, under vacuum) before the actual reaction is started in order to remove any isopropanol residues present from the precursors, which would otherwise lead to unwanted by-products. Reaction: stirring for 1.5-3 hours, preferably 2 hours. For the work-up, water is added directly to the mixture, where the product crystallizes out. In order to have a particularly stable and reproducible process, a first portion of water (for example 1 / 3) is added first, then seed crystals are added, and the remaining amount of water is added. This procedure guarantees that always the same crystal polymorph is obtained, which shows the best separation properties. The product is washed with water and dried. The yield is > 92% of theory.

[0046] Starting from ethyl ether (XI), the acid (XII) is obtained by basic saponification and subsequent acidic work-up.

[0047]

[0048] In the research scale synthesis, the saponification was carried out in a mixture of DME / water 3:1 at a high dilution (33.9 times). Here, first the throughput had to be increased and the used DME (dimethoxyethane) replaced, which has a very low flash point and therefore is considered to be particularly critical for large scale use. Surprisingly, it was found that the reaction can also be carried out very easily in a highly concentrated manner in a mixture of THF / water. For this purpose, the reaction is preferably carried out in a mixture of THF / water 2:1 (9 times), an aqueous sodium hydroxide solution is added at 0-5°C, then the mixture is stirred at 0-5°C for 1-2 hours. An aqueous potassium hydroxide solution can also be used, but the use of NaOH is preferred. For the work-up, the mixture is extracted with MTBE (methyl tert-butyl ether) and ethyl acetate, in order to isolate, the pH is adjusted to pH 6.5-7.0 or pH 7 with a mineral acid, for example hydrochloric acid, sulfuric acid or phosphoric acid, but preferably hydrochloric acid. Then the mixture is mixed with a saturated ammonium salt solution of the corresponding acid, but preferably with an ammonium chloride solution, in which the product crystallizes out quantitatively. After separation, the product is washed with water and with ethyl acetate or acetonitrile or acetone, but preferably with acetonitrile, and dried at 40-50°C under vacuum. The yield is almost quantitative (99%). Another preferred work-up: As an alternative work-up, toluene is added to the mixture, sodium acetate is added and the mixture is stirred at 20°C, then the phases are separated and the aqueous phase is adjusted to pH 6.5-7.0 at 0°C with a 10% aqueous hydrochloric acid solution (crystallization seeds can optionally be added at pH 9.5-10). The mixture is stirred a little, the product is filtered off, washed with a little water and toluene, and dried at 40-50°C under vacuum. In this case, too, a quantitative yield is achieved.

[0049] In the research phase, the subsequent conversion of the acid to the amide (XIII) was carried out as follows: The acid (XII) was dissolved in about 10 times DMF, 1.25 equivalents of 1,1'- carbonyldiimidazole and 0.1 equivalents of DMAP (4-(dimethylamino)pyridine) were added and the mixture was stirred at room temperature for 4 hours. Subsequently, 20 equivalents of ammonia in the form of a 25% aqueous solution were added and the mixture was transferred to an oil bath preheated to 110°C. In this procedure, a relatively large amount of ammonia gas was formed immediately, which escaped from the system and also ensured a sharp increase in pressure. The mixture was added to about 90 times water and adjusted to pH 7 by adding sodium acetate. The precipitated product was filtered off and dried (yield: 59% of the theoretical value). Another fraction was separated from the mother liquor by exhaustive extraction (about 100 times ethyl acetate), which was stirred together with highly flammable diethyl ether and contained about 14% DMF. It is clear that such a method cannot be realized in this way in an operating framework, therefore, a replacement procedure is highly desirable. In this case, the effort required to isolate this fraction is not proportional to the amount isolated.

[0050]

[0051] Surprisingly, it has been found that in the reaction of the acid (XII) in THF, the amide (XIII) crystallizes directly from the solution and can be obtained in high yield and purity. For this purpose, the carboxylic acid (XII) is reacted with 1.1 to 1.6 equivalents, preferably 1.3-1.4 equivalents, of 1,1'-carbonyldiimidazole in THF catalyzed by DMAP (5-15 mol%, preferably 10 mol%) to give the imidazolide, which has proven to be the preferred method: initially at 20°C, then stirring at this temperature for 1 to 2 hours, then further stirring at 50°C for 2 to 3 hours. After completion of the activation, 3-8 equivalents, preferably 4.5 equivalents, of hexamethyldisilazane are added and the mixture is boiled under reflux for 16-24 hours, but preferably for 16 hours. Here, the resulting disilylamide compound can optionally be isolated, but it has proven to be advantageous to continue in a one-pot reaction. Thus, after completion of the reaction, the mixture is cooled to 0-3°C and a mixture of water and / or a mixture of water and THF is added, it has proven to be advantageous to use an amount of 0.5 to 0.7 times the amount of water (relative to the reactants), in particular 0.52 times the amount of water. The water can be added directly or as a mixture in an amount of up to twice the volume of THF. After completion of the quenching, the mixture is heated under reflux for a total of 1-3 hours, preferably 1 hour. The mixture is cooled to 0°C and stirred at this temperature for 1-5 hours, preferably 3 hours, then the product is isolated by filtration or centrifugation. The product is washed with THF and water and dried under vacuum at elevated temperature (30 to 100°C, preferably 60°C to 90°C or 40°C to 70°C). The yield is very high, usually > 93% of the theoretical value. The purity is usually > 99% (HPLC, 100% method). Compound (XIII) can also be obtained directly by reaction with ammonia in an autoclave (about 25 to 30 bar). For this purpose, the pre-activation described above is carried out and the reaction mixture is heated under pressure with gaseous ammonia. As soon as the reaction is complete, it is cooled and the product is filtered off. The yield and purity achieved thereby are comparable.

[0052] To obtain the compounds of the formula (I), the racemic mixture of the amide (XIII) has to be separated into the enantiomers. In the published synthesis on research scale, for this purpose a specific synthetic chiral phase (in-house preparation) is used, which contains N-(dicyclopropylmethyl)-N 2- methacryl-D-leucinamide as chiral selector. This selector is prepared in a multi-stage process and then polymerized on special silica gel. Methanol / ethyl acetate as eluent. The main disadvantage of this method is the very low sample size - 30 mg per separation on a 500 x 63 mm chromatographic column, which makes it very desirable to find a separation method that is as efficient as possible, which can be carried out on a multi-ton scale of enantiomers. Surprisingly, it has been found that the separation can be carried out on an easily commercially available phase. It takes the form of the phase Chiralpak AS-V, 20 μm. The eluent used is a mixture of methanol / acetonitrile 60:40. The main advantage of this mixture is that after distillation treatment it can be recovered as an eluent with the same composition (60:40 corresponds to the azeotrope). In this way a very efficient process is achieved, in which the yield of separation is > 47% of the theoretical value (theoretically it can be 50%). Here, the optical purity is > 93% e.e., but preferably > 98.5% e.e.. In this case, the chromatography can be carried out on a conventional chromatographic column, but preferably using techniques known to the person skilled in the art, such as SMB or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901). For example, 500 kg of the racemic amide (XIII) are separated using an SMB system, in which the yield reaches 48%. The product obtained is a solution of 3-8%, preferably 5-7%, in a mixture of methanol / acetonitrile 60:40, and can be used directly in the "final treatment". Other solvent mixtures of acetonitrile with methanol are also possible (90:10 to 10:90). However, for the SMB separation, or other solvent mixtures can also be used, such as acetonitrile / ethanol in a mixture ratio of 10:90 to 90:10. The specific solvent ratio depends partly on the technical properties of the SMB system and must be adjusted if appropriate (e.g. change in flow rate, recovery of solvent on thin-film evaporator).

[0053]

[0054] Since the compound of formula (I) has been developed in the form of tablets, it is very desirable to separate the separated compound of formula (I) in a reproducible manner in a defined crystal form, so that a reproducible bioavailability can be ensured. Surprisingly, it has been found that the compound of formula (I) can be crystallized from methanol, ethanol, THF, acetonitrile and mixtures thereof with water, in which only one polymorph I is reproducibly formed, which has a defined melting point of 252°C. Advantageously, ethanol or denatured ethanol is used.

[0055] Final crystallization process: For this purpose, for GMP-technical reasons, about 5-7% of the product originating from the chromatography is first of all subjected to a particle filtration in a solution of methanol / acetonitrile 60:40 (or, if ethanol / acetonitrile is used, about 3-4% of a solution of ethanol / acetonitrile 50:50) and then subjected to a solvent exchange with ethanol, preferably with ethanol denatured with toluene. For this purpose, the solution is repeatedly redistilled, concentrated and each time fresh ethanol is added. After the exchange, as much ethanol as possible is added until the solution flows at the boiling point, and then it is concentrated to about 3 to 4 times the volume at atmospheric pressure or at slightly reduced pressure, whereupon the product crystallizes out. It is cooled to 0°C, and then the crystals are separated and dried in a vacuum at 40-50°C. The yield is usually > 90% of the theoretical value. The chemical purity achieved is > 99.8%, the content is ~ 100%, and the ICH guidelines are met for the standard of a commercial product. In the case of ethanol, the residual solvent is < 0.02%. The optical purity is >> 99% e.e.

[0056] The present application provides a compound of formula (I) in crystalline form of polymorph I

[0057]

[0058] characterized in that the X-ray diffractogram of the compound has peak maxima at 2 theta angles of 8.5, 14.1, 17.2, 19.0, 20.5, 25.6, 26.5.

[0059] The present application provides a compound of formula (I) in crystalline form of polymorph I

[0060]

[0061] characterized in that the IR spectrum (IR-ATR) of the compound has band maxima at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136 and 1031 cm -1 .

[0062] The present application provides a compound of formula (I) in crystalline form of polymorph I

[0063]

[0064] characterized in that the Raman spectrum of the compound has band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827 and 155 cm -1 .

[0065] The present application also provides a process for the preparation of the compound of formula (I) in crystalline form of polymorph I, characterized in that the compound of formula (I) which is present in the form of one or more polymorphs or in the form of a solvate is stirred in an inert solvent at a temperature of from 20°C to 120°C and the compound of formula (I) in crystalline polymorph I is isolated.

[0066] The preferred solvents for the process for the preparation of the compound of formula (I) in crystalline form of polymorph I are methanol, ethanol, THF, acetonitrile and mixtures thereof. Ethanol or denatured ethanol are particularly preferred.

[0067] The preferred temperature range for the process for the preparation of the compound of formula (I) in crystalline form of polymorph I is from 20°C to 90°C.

[0068] The present application also provides the compound of formula (I) in crystalline form of polymorph (I) as described above for use in the treatment of a disease.

[0069] The present application also provides a medicament comprising the compound of formula (I) in crystalline form of polymorph (I) as described above and no greater proportion of any other form of the compound of formula (I) in crystalline form of polymorph (I) as described above. The present application also provides a medicament comprising more than 90% by weight of the compound of formula (I) in crystalline form of polymorph (I) as described above, based on the total amount of the compound of formula (I) present in crystalline form of polymorph (I) as described above.

[0070] The present application also provides the use of the compound of formula (I) in crystalline form of polymorph I as described above for the preparation of a medicament for the treatment of a cardiovascular disease.

[0071] The present application also provides a method for the treatment of a cardiovascular disease by administering an effective amount of the compound of formula (I) in crystalline form of polymorph (I) as described above.

[0072] The present application also provides a process for the preparation of compound (I), characterized in that a compound of formula (XIV) or (XIVa)

[0073]

[0074] to give a compound of formula (XV) or (XVa)

[0075]

[0076] The non-isolated methyl ester of formula (XV) or (XVa) is reduced with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminiumhydride) and 1.28 equivalents of N-methylpiperazine to give the aldehyde of formula (XVI) or (XVIa)

[0077]

[0078] and the aldehyde (XVI) or (XVIa) is further reacted without isolation to give the nitrile of formula (VI)

[0079]

[0080] The present application also provides a process for the preparation of a compound of formula (I) characterized in that a compound of formula (VI)

[0081]

[0082] is reacted with a compound of formula (VII)

[0083]

[0084]

[0085] to give the compound (VIIIa+b)

[0086]

[0087] The present application also provides a process for the preparation of a compound of formula (I) characterized in that a compound of formula (X)

[0088]

[0089] is reacted with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours to give the compound of formula (XI)

[0090]

[0091] The present application also provides a process for the preparation of a compound of formula (I) characterized in that a compound of formula (XI)

[0092]

[0093] is saponified with aqueous sodium hydroxide in a THF / water mixture (2:1, 9 times) to give the compound of formula (XII)

[0094]

[0095] The present application also provides a process for the preparation of a compound of formula (I) characterized in that a compound of formula (XII)

[0096]

[0097] first with carbonyldiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF, in a second step with hexamethyldisilazane under reflux for 16 to 24 hours and in a third step hydrolysis in water or water containing THF to give a compound of formula (XIII)

[0098]

[0099] The present application also provides a process for the preparation of a compound of formula (I) characterized in that a compound of formula (XIV) or (XIVa) is reacted by addition of dimethyl sulfate

[0100]

[0101] to give a compound of formula (XV) or (XVa)

[0102]

[0103] The non-isolated methyl ester of formula (XV) or (XVa) is reduced with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminum dihydride) and 1.28 equivalents of N-methylpiperazine to give an aldehyde of formula (XVI) or (XVIa)

[0104]

[0105] and the aldehyde (XVI) or (XVIa) is further reacted without isolation to give a nitrile of formula (VI)

[0106]

[0107] and the compound of formula (VI) is dissolved in isopropanol (3-7 times), 5-10 mole % piperidine and 5-10 mole % glacial acetic acid at 30°C

[0108]

[0109] with a compound of formula (VII)

[0110]

[0111] to give a compound (VIIIa+b)

[0112]

[0113] The present application also provides a process for the preparation of a compound of formula (I) characterized in that a compound of formula (VI)

[0114]

[0115]

[0116] is reacted with a compound of formula (VII)

[0117]

[0118] to give a compound (VIIIa+b)

[0119]

[0120] and characterized in that a compound of formula (X)

[0121]

[0122] is reacted with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours to give a compound of formula (XI)

[0123]

[0124] The present application also provides a process for the preparation of a compound of formula (I) characterized in that a compound of formula (X)

[0125]

[0126] is reacted with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours to give a compound of formula (XI)

[0127]

[0128] and characterized in that a compound of formula (XI)

[0129]

[0130] is saponified with an aqueous sodium hydroxide solution in a THF / water mixture (2:1, 9 times) to give a compound of formula (XII)

[0131]

[0132]

[0133] The present application also provides a process for the preparation of a compound of formula (I), characterized in that a compound of formula (XI)

[0134]

[0135] is saponified with an aqueous sodium hydroxide solution in a THF / water mixture (2:1, 9-fold) to give a compound of formula (XII)

[0136]

[0137] and characterized in that a compound of formula (XII) is reacted in a one-pot reaction with

[0138]

[0139] first with carbonyldiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF, in a second step with hexamethyldisilazane under reflux for 16 to 24 hours, and in a third step hydrolyzed in water or in water containing THF to give a compound of formula (XIII)

[0140]

[0141] The present application also provides a process for the preparation of a compound of formula (I), characterized in that a compound of formula (XIV) or (XIVa)

[0142]

[0143] is reacted by addition of dimethyl sulfate to give a compound of formula (XV) or (XVa)

[0144]

[0145] The non-isolated methyl ester of formula (XV) or (XVa) is reduced with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminum dihydride) and 1.28 equivalents of N-methylpiperazine to give an aldehyde of formula (XVI) or (XVIa)

[0146]

[0147] and the aldehyde (XVI) or (XVIa) is further reacted without isolation to give a nitrile of formula (VI)

[0148]

[0149] And compounds of formula (VI) that dissolve at 30°C in isopropanol (3-7 times), 5-10 mol% piperidine, and 5-10 mol% glacial acetic acid.

[0150]

[0151] Reaction with compounds of formula (VII)

[0152]

[0153] To obtain compound (VIIIa+b)

[0154]

[0155] And it is characterized by causing the compound of formula (X) to react at 100 to 120°C.

[0156]

[0157] The compound was reacted with 2.5–5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours to give the compound of formula (XI).

[0158]

[0159] The present invention also provides a method for preparing a compound of formula (I), characterized in that the compound of formula (VI) is dissolved in isopropanol (3-7 times), 5-10 mol% piperidine, and 5-10 mol% glacial acetic acid at 30°C.

[0160]

[0161] Reaction with compounds of formula (VII)

[0162]

[0163] To obtain compound (VIIIa+b)

[0164]

[0165] And it is characterized by causing the compound of formula (X) to react at 100 to 120°C.

[0166]

[0167] The compound was reacted with 2.5–5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours to give the compound of formula (XI).

[0168]

[0169] and characterized in that the compound of the formula (XI)

[0170]

[0171] saponification with aqueous sodium hydroxide in a THF / water mixture (2:1, 9-fold) to give the compound of the formula (XII)

[0172]

[0173]

[0174] The application also provides a process for the preparation of a compound of the formula (I), characterized in that the compound of the formula (X)

[0175]

[0176] with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours to give the compound of the formula (XI)

[0177]

[0178] and characterized in that the compound of the formula (XI)

[0179]

[0180] saponification with aqueous sodium hydroxide in a THF / water mixture (2:1, 9-fold) to give the compound of the formula (XII)

[0181]

[0182] and characterized in that the compound of the formula (XII)

[0183]

[0184] first with carbonyldiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF, in a second step with hexamethyldisilazane under reflux for 16 to 24 hours and in a third step hydrolysis in water or water with THF to give the compound of the formula (XIII)

[0185]

[0186] The application also provides a process for the preparation of a compound of the formula (I), characterized in that the compound of the formula (XIV) or (XIVa)

[0187]

[0188]

[0189] to give a compound of formula (XV) or (XVa)

[0190]

[0191] The non-isolated methyl ester of formula (XV) or (XVa) is reduced with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminum dihydride) and 1.28 equivalents of N-methylpiperazine to give the aldehyde of formula (XVI) or (XVIa)

[0192]

[0193] and the aldehyde (XVI) or (XVIa) is further reacted without isolation to give the nitrile of formula (VI)

[0194]

[0195] and the compound of formula (VI) is dissolved in isopropanol (3-7 times), 5-10 mole % piperidine and 5-10 mole % glacial acetic acid at 30°C

[0196]

[0197] with a compound of formula (VII)

[0198]

[0199]

[0200] to give the compound (VIIIa+b)

[0201]

[0202] and characterized in that the compound of formula (X) is reacted with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours at 100 to 120°C to give the compound of formula (XI)

[0203]

[0204] and characterized in that the compound of formula (XI) is reacted with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours at 100 to 120°C to give the compound of formula (XI)

[0205]

[0206] and characterized in that the compound of formula (XI) is reacted with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours at 100 to 120°C to give the compound of formula (XI)

[0207]

[0208]

[0209] saponification with aqueous sodium hydroxide in a THF / water mixture (2:1, 9 times) to give a compound of formula (XII)

[0210]

[0211] The present application also provides a process for the preparation of a compound of formula (I) characterised in that a compound of formula (VI)

[0212]

[0213] is reacted with a compound of formula (VII)

[0214]

[0215] to give compounds (VIIIa+b)

[0216]

[0217] and characterised in that a compound of formula (X)

[0218]

[0219] is reacted with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours at 100 to 120°C to give a compound of formula (XI)

[0220]

[0221] and characterised in that a compound of formula (XI)

[0222]

[0223] is saponified with aqueous sodium hydroxide in a THF / water mixture (2:1, 9 times) to give a compound of formula (XII)

[0224]

[0225]

[0226] and characterised in that a compound of formula (XII)

[0227]

[0228] first with carbonyldiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF, in a second step with hexamethyldisilazane under reflux for 16 to 24 hours, and in a third step hydrolysis in water or water with THF to give the compound of formula (XIII)

[0229]

[0230] The present application also provides a process for the preparation of a compound of formula (I), characterized in that the compound of formula (XIV) or (XIVa) is reacted by addition of dimethyl sulfate

[0231]

[0232] to give the compound of formula (XV) or (XVa)

[0233]

[0234] and the non-isolated methyl ester of formula (XV) or (XVa) is reduced with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminum dihydride) and 1.28 equivalents of N-methylpiperazine to give the aldehyde of formula (XVI) or (XVIa)

[0235]

[0236] and the aldehyde (XVI) or (XVIa) is further reacted without isolation to give the nitrile of formula (VI)

[0237]

[0238] and the compound of formula (VI) is dissolved in isopropanol (3-7 times), 5-10 mol% piperidine and 5-10 mol% glacial acetic acid at 30°C

[0239]

[0240] with the compound of formula (VII)

[0241]

[0242] to give the compound (VIIIa+b)

[0243]

[0244] and characterized in that the compound of formula (X) is reacted with the compound of formula (XI)

[0245]

[0246] with 2.5 to 5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring for 1.5 to 3 hours to give a compound of formula (XI)

[0247]

[0248] and characterized in that a compound of formula (XI)

[0249]

[0250]

[0251] is saponified with aqueous sodium hydroxide in a THF / water mixture (2:1, 9-fold) to give a compound of formula (XII)

[0252]

[0253] and characterized in that a compound of formula (XII)

[0254]

[0255] is first reacted with carbonyldiimidazole and a catalytic amount of 4- (dimethylamino)pyridine in THF, in a second step with hexamethyldisilazane under reflux for 16 to 24 hours, and in a third step hydrolyzed in water or water with THF to give a compound of formula (XIII)

[0256]

[0257] The crystallization process is very robust and gives the compound of formula I in crystalline form of polymorph I (m.p. 252°C) in a reproducible manner. Surprisingly, also lower optical purity of the material can be used in the crystallization process and it turned out that even a material of 93% e.e. still gives >99% e.e. after crystallization.

[0258] The compound of formula (I) is usually micronized and formulated as a medicament. We found that the compound of formula (I) in crystalline form of polymorph I has a very good stability (even at high atmospheric humidity) and can be stored without problems for >2 years.

[0259] By the new synthesis method of the present application, the compound of formula (I) can be prepared in a very efficient manner. Compared to the prior art, the method offers considerable advantages in terms of scale-up and technical performance. The overall yield is significantly higher compared to the published data and the active ingredient also reaches an excellent purity. The new method enables the reproducible, economic production of the compound of formula (I) in crystalline form of polymorph I, which is not described in the prior art.

[0260] Using the process of the application presented herein, 200 kg of material has been successfully prepared for clinical trials.

[0261] The compounds of the application, the compounds of formula (I) as well as the compounds of formula (I) in the crystalline form of polymorph I, act as antagonists of the mineralocorticoid receptor and exhibit an unpredictable, useful spectrum of pharmacological activity. They are therefore suitable for use as medicaments for the treatment and / or prevention of disorders in humans and animals.

[0262] The compounds of the application are suitable for the prevention and / or treatment of various disorders as well as disease-related conditions, in particular disorders characterized by an increased or a change in plasma aldosterone concentration relative to plasma renin concentration, or disorders associated with these changes. Examples include: idiopathic primary aldosteronism, aldosteronism associated with adrenal hyperplasia, adrenal adenoma and / or adrenal carcinoma, aldosteronism associated with cirrhosis, aldosteronism associated with heart failure, and (relative) aldosteronism associated with primary hypertension.

[0263] Due to their mechanism of action, the compounds of the application are also suitable for the prevention of sudden cardiac death in patients at increased risk of dying from sudden cardiac death. In particular, these patients are patients suffering from one of the following disorders: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, treatment-resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, dilative cardiomyopathy, hereditary primary cardiomyopathy (e.g. Brugada syndrome), Chagas' disease-induced cardiomyopathy, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, peripheral flow disorders, arterial occlusive disorders such as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis, cardiac hypertrophic changes, pulmonary arterial hypertension, coronary and peripheral arterial spasm, thrombosis, thromboembolic disorders, and vasculitis.

[0264] The compounds of the application are also useful for the prevention and / or treatment of edema formation, such as pulmonary edema, renal edema or edema associated with heart failure, and restenosis such as restenosis after thrombolytic therapy, after percutaneous transluminal angioplasty (PTA) and percutaneous transluminal coronary angioplasty (PTCA), after heart transplantation and bypass surgery.

[0265] The compounds of the application are also suitable for use as potassium-sparing diuretics and for electrolyte disorders, such as hypercalcemia, hypernatremia or hypokalemia.

[0266] The compounds according to the application are also suitable for the treatment of kidney disorders, such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal insufficiency and also cystic kidney disorders, for the prevention of renal impairment (in the case of organ transplantation, which can be caused, for example, by immunosuppressants such as cyclosporin A), and for kidney cancer.

[0267] The compounds according to the application can also be used for the prevention and / or treatment of diabetes and diabetic sequelae, such as neuropathy and nephropathy.

[0268] The compounds according to the application can also be used for the prevention and / or treatment of microalbuminuria (for example caused by diabetes or hypertension) and also proteinuria.

[0269] The compounds according to the application are also suitable for the prevention and / or treatment of disorders associated with an increased plasma glucocorticoid concentration or with a local increase in the glucocorticoid concentration in a tissue, for example the heart. Examples include: adrenal dysfunction leading to an excess production of glucocorticoids (Cushing syndrome), adrenal cortex tumours which cause an excess production of glucocorticoids, and pituitary tumours which spontaneously produce ACTH (adrenocorticotropic hormone) and thus cause adrenal hyperplasia leading to Cushing disease.

[0270] The compounds according to the application can also be used for the prevention and / or treatment of obesity, metabolic syndrome and obstructive sleep apnoea.

[0271] The compounds according to the application can also be used for the prevention and / or treatment of inflammatory disorders caused, for example, by viruses, spirochaetes, fungi, bacteria or mycobacteria, and also inflammatory disorders of unknown aetiology, such as polyarthritis, lupus erythematosus, periarteritis or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.

[0272] The compounds according to the application can also be used for the treatment of central nervous disorders such as depression, anxiety states and chronic pain, in particular migraine, and also for neurodegenerative disorders such as Alzheimer's disease and Parkinson's syndrome.

[0273] The compounds according to the application are also suitable for the prevention and / or treatment of vascular damage, for example after an operation such as percutaneous transluminal coronary angioplasty (PTCA), stent implantation, coronary angioscopy, reocclusion or restenosis after a bypass operation, and also for endothelial dysfunction, Raynaud's disease, thromboangiitis obliterans (Buerger's syndrome) and tinnitus syndrome.

[0274] The application also provides the use of the compounds according to the application for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[0275] The present application also provides the use of a compound of the present application for the preparation of a medicament for the treatment and / or prophylaxis of a disorder, in particular of a disorder as described above.

[0276] The present application also provides a method for the treatment and / or prophylaxis of a disorder, in particular of a disorder as described above, using an effective amount of at least one compound of the present application.

[0277] The compounds of the present application can be used alone or, if desired, in combination with other active compounds. The present application also provides medicaments comprising at least one compound of the present application and one or more further active compounds, in particular active compounds for the treatment and / or prophylaxis of a disorder as described above. Preferred examples of active compounds suitable for combination include:

[0278] • active compounds that lower blood pressure, such as and preferably selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers and Rho kinase inhibitors;

[0279] • diuretics, especially loop diuretics, and thiazides and thiazide-like diuretics;

[0280] • antithrombotic agents, such as and preferably selected from the group consisting of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;

[0281] • active compounds that alter lipid metabolism, such as and preferably selected from the group consisting of thyroid receptor agonists, cholesterol synthesis inhibitors (such as and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors), ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists;

[0282] • organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

[0283] • compounds with positive inotropic action, such as cardiac glycosides (digoxin), beta-adrenergic agonists and dopaminergic agonists such as isoprenaline, adrenaline, noradrenaline, dopamine and dobutamine;

[0284] • Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterases (PDEs) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil and PDE 3 inhibitors such as amrinone and milrinone;

[0285] • Natriuretic peptides, for example "atrial natriuretic peptide" (ANP, anaritide), "B-type natriuretic peptide" or "brain natriuretic peptide" (BNP, nesiritide), "C-type natriuretic peptide" (CNP) and urodilatin;

[0286] • Calcium sensitizers, a preferred example being levosimendan;

[0287] • Guanylate cyclase stimulators which are independent of NO but dependent on haem, such as the compounds described in particular in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301 and WO 03 / 095451 ;

[0288] • Guanylate cyclase activators which are independent of NO and haem, such as the compounds described in particular in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510;

[0289] • Inhibitors of human neutrophil elastase (HNE), for example sivelestat or DX-890 (Reltran);

[0290] • Compounds which inhibit the signal transduction cascade, for example tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and / or

[0291] • Compounds which influence the energy metabolism of the heart, a preferred example being etomoxir, dichloroacetate, ranolazine or trimetazidine.

[0292] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a diuretic, such as and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0293] An agent lowering blood pressure is preferably understood to mean a compound selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, Rho kinase inhibitors and diuretics.

[0294] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a calcium antagonist, such as and preferably nifedipine, amlodipine, verapamil or diltiazem.

[0295] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with an angiotensin AII antagonist, preferred examples of which are losartan, candesartan, valsartan, telmisartan or embusartan.

[0296] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with an ACE inhibitor, for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

[0297] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with an endothelin antagonist, for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.

[0298] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a renin inhibitor, a preferred example of which is aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.

[0299] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with an alpha-1 -receptor blocker, for example and preferably prazosin.

[0300] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a beta-receptor blocker, such as and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0301] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a rho-kinase inhibitor, such as and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

[0302] An antithrombotic agent (antithrombotic drug) is preferably understood to mean a compound selected from the group consisting of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

[0303] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a platelet aggregation inhibitor, such as and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

[0304] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a thrombin inhibitor, such as and preferably ximelagatran, melagatran, bivalirudin or clexane.

[0305] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a GPIIb / IIIa antagonist, such as and preferably tirofiban or abciximab.

[0306] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a Factor Xa inhibitor, such as and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0307] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0308] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a vitamin K antagonist, such as and preferably coumarin.

[0309] Lipid metabolism modulators are preferably understood to mean compounds selected from the group consisting of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, sequestrants of polymeric bile acids, inhibitors of the reabsorption of bile acids, lipase inhibitors and lipoprotein (a) antagonists.

[0310] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a CETP inhibitor, such as and preferably torcetrapib (CP-529 414), JTT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant).

[0311] In a preferred embodiment of the application, the compounds of the present application are administered in combination with a thyroid receptor agonist, such as and preferably D- thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

[0312] In a preferred embodiment of the application, the compounds of the present application are administered in combination with an HMG-CoA reductase inhibitor from the statin class, such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

[0313] In a preferred embodiment of the application, the compounds of the present application are administered in combination with a squalene synthesis inhibitor, such as and preferably BMS-188494 or TAK-475.

[0314] In a preferred embodiment of the application, the compounds of the present application are administered in combination with an ACAT inhibitor, such as and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[0315] In a preferred embodiment of the application, the compounds of the present application are administered in combination with an MTP inhibitor, such as and preferably implitapide, BMS-201038, R-103757 or JTT-130.

[0316] In a preferred embodiment of the application, the compounds of the present application are administered in combination with a PPAR-gamma agonist, such as and preferably pioglitazone or rosiglitazone.

[0317] In a preferred embodiment of the application, the compounds of the present application are administered in combination with a PPAR-delta agonist (preferred examples are GW 501516 or BAY 68-5042).

[0318] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe, tiqueside or pamaqueside.

[0319] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a lipase inhibitor, such as and preferably orlistat.

[0320] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a polymeric bile acid adsorber, such as and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

[0321] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a bile acid reabsorption inhibitor, such as and preferably an ASBT (= IBAT) inhibitor, e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0322] In a preferred embodiment of the present application, the compounds of the present application are administered in combination with a lipoprotein (a) antagonist, such as and preferably gemcabene calcium (CI-1027) or niacin.

[0323] The present application also provides medicaments comprising at least one compound of the present application, usually together with one or more inert, nontoxic, pharmaceutically suitable excipients, and the use thereof for the above-mentioned purposes.

[0324] The compounds of the present application can act systemically and / or locally. For this purpose, they can be administered in a suitable manner, e.g. by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, intradermal, transdermal, conjunctival or aural route, or as an implant or stent.

[0325] The compounds of the present application can be administered in a form suitable for these administration routes.

[0326] Suitable administration forms for oral administration are administration forms which function according to the prior art and release the compounds of the application rapidly and / or in a modified manner and contain the compounds of the application in crystalline and / or amorphous and / or dissolved form, for example tablets (uncoated or film-coated tablets, for example with a stomach fluid-resistant or delayed-dissolution or dissolution- resistant coating), rapidly disintegrating tablets or films / oblates, films / lyophilisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0327] Parenteral administration can be performed with avoidance of an absorption step (for example by intravenous, intraarterial, intracardiac, intraspinal or intralumbar routes) or with inclusion of an absorption step (for example by intramuscular, subcutaneous, intracutaneous, transdermal or intraperitoneal routes). Administration forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0328] For other administration routes, suitable examples are inhalable pharmaceutical forms (including powder inhalers, nebulizers), nose drops, solutions or sprays; tablets, films / oblates or capsules for lingual, sublingual or buccal administration; suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example plasters), milks, pastes, foams, sprinkling powders, implants or stents.

[0329] Oral and parenteral administration, especially oral and intravenous administration, are preferred.

[0330] The compounds of the application can be converted to the administration forms described. This can be achieved with the aid of known methods by mixing with inert, nontoxic, pharmaceutically suitable excipients. These excipients include carriers such as microcrystalline cellulose, lactose, mannitol; solvents such as liquid polyethylene glycols; emulsifiers and dispersants or wetting agents such as sodium dodecyl sulfate, polyoxy sorbitol oleate; binders such as polyvinylpyrrolidone; synthetic and natural polymers such as albumin; stabilizers such as antioxidants, for example ascorbic acid; colorants such as inorganic pigments, for example iron oxides; and flavourings and / or odour correctants.

[0331] Generally, it has been found to be advantageous, in the case of parenteral administration, to administer an amount of from about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg, of body weight to achieve effective results. In the case of oral administration, the dosage is from about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and very particularly preferably 0.1 to 10 mg / kg of body weight.

[0332] However, it can be necessary to deviate from the amounts stated, depending inter alia on the body weight, the route of administration, the individual response to the active compound, the nature of the formulation and the time or interval over which the administration is carried out. It is therefore possible for less than the minimum amount stated above to be sufficient in some cases, whilst in other cases it can be necessary to exceed the upper limit stated. In the case of larger amounts, it can be advisable to divide these into several individual doses over the day.

[0333] The following working examples illustrate the application. The application is not limited to the examples.

[0334] The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are in each case based on volume. DETAILED DESCRIPTION

[0335] Experimental Part

[0336] Abbreviations and acronyms:

[0337] MS: mass obtained by mass spectrometry

[0338] HPLC: high-performance liquid chromatography

[0339] DMF: dimethylformamide

[0340] Solution of Red-Al in toluene: sodium bis(2-methoxyethoxy)aluminium dihydride in toluene

[0341] THF: tetrahydrofuran

[0342] aq. HCI: aqueous hydrochloric acid

[0343] DMAP: 4-(dimethylamino)pyridine

[0344] Examples

[0345] Example 1

[0346] 4-bromo-2-methoxybenzoic acid methyl ester (XV)

[0347] First 3.06 kg (22.12 mol) of potassium carbonate are added to 3.6 I of acetone and heated to reflux. To this suspension 1.2 kg of 4-bromo-2-hydroxybenzoic acid (5.53 mol) suspended in 7.8 I of acetone are added and rinsed with a further 0.6 I of acetone. The suspension is heated under reflux for 1 h (vigorous gas evolution!). Then 2.65 kg (21.01 mol) of dimethyl sulfate are added over 4 h while boiling. Subsequently the mixture is stirred under reflux for 2.5 h. Most of the solvent is distilled off (to a stirrable consistency), 12 I of toluene are added and then the residual acetone is distilled off at 110 °C. About 3 I of distillate are distilled off which is replenished by adding a further 3 I of toluene to the mixture. The mixture is allowed to cool to 20 °C, 10.8 I of water are added and stirred vigorously. The organic phase is separated, the aqueous phase is re-extracted once with 6.1 I of toluene. The combined organic phases are washed with 3 I of saturated sodium chloride solution and the toluene phase is concentrated to about 4 I. The content is determined by evaporating a portion to give a conversion yield of 1.306 kg (96.4% of theory). The solution is used directly in the subsequent stage.

[0348] HPLC Method A: RT about 11.9 min.

[0349] MS (EI pos): m / z = 245 [M+H] +

[0350] 1 H NMR (400 MHz, CD2CI2): δ = 3.84 (s, 3H), 3.90 (s, 3H), 7.12-7.20 (m, 2H), 7.62 (d, 1H).

[0351] Example 2

[0352] 4-bromo-2-methoxybenzaldehyde (XVI)

[0353] To a solution of 1.936 kg (6.22 mol) of 65% Red-Al in toluene at -5°C, 1.25 1 of toluene were added. To this solution, 0.66 kg (6.59 mol) of 1-methylpiperazine were added, rinsing with 150 ml of toluene while maintaining the temperature at -7 to -5°C. The mixture was then stirred for 30 minutes at 0°C. This solution was then added to a solution of 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV) dissolved in 4 1 of toluene, while maintaining the temperature at -8 to 0°C. After two additional rinsings with 0.7 1 of toluene, the mixture was then stirred for 1.5 hours at 0°C. For the work-up, the solution was added to a cold aqueous sulfuric acid solution (12.5 1 of water + 1.4 kg of concentrated sulfuric acid) at 0°C. The temperature should rise to a maximum of 10°C (slow addition). If necessary, the pH is adjusted to pH 1 by adding additional sulfuric acid. The organic phase is separated out and the aqueous phase is extracted with 7.6 1 of toluene. The combined organic phases are washed with 5.1 1 of water, then concentrated well and the residue is dissolved in 10 1 of DMF. The solution is concentrated again to a volume of about 5 1. The content is determined by evaporation of a portion, giving a conversion yield of 1.041 kg (94.1% of theory). The solution is used directly for the subsequent stage.

[0354] HPLC Method A: RT about 12.1 min.

[0355] MS (EI pos): m / z = 162 [M+H] +

[0356] 1 H-NMR (CDCI3, 400 MHz): δ = 3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d), 10.40 (1H, s)

[0357] Example 3

[0358] 4-formyl-3-methoxybenzonitrile (VI)

[0359] To a solution of 719 g (3.34 mol) 4-bromo-2-methoxybenzaldehyde (XVI) in 4.5 1 DMF were added 313 g (0.74 mol) potassium hexacyanoferrate (K4[Fe(CN)6]) and 354 g (3.34 mol) sodium carbonate and additionally 1.2 1 DMF and 3.8 g (0.017 mol) palladium acetate. The mixture was stirred at 120 °C for 3 hours. The mixture was allowed to cool to 20 °C and 5.7 1 water were added to the mixture. The mixture was extracted with 17 1 ethyl acetate and the aqueous phase was washed once more with 17 1 ethyl acetate. The organic phases were combined and concentrated thoroughly, dissolved in 5 1 isopropanol and concentrated to about 2 1. The mixture was heated to boiling and 2 1 water were added dropwise. The mixture was allowed to cool to 50 °C and another 2 1 water were added. The mixture was cooled to 3 °C and stirred at this temperature for 1 hour. The product was filtered off and washed with water (2 times, 1.2 1). The product was dried in vacuum at 40 °C.

[0360] Yield: 469 g (87% of theory) beige solid.

[0361] HPLC Method A: RT about 8.3 min.

[0362] MS (EI pos): m / z = 162 [M+H]+

[0363] 1H-NMR (300 MHz, DMSO-d6): δ = 3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).

[0364] Example 4

[0365] 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6- naphthyridine-3-carboxylic acid 2-cyanoethyl ester (X) Variant A

[0366] Variant B

[0367] In a water separator, 1.035 kg (6.422 mol) of 4-formyl-3-methoxybenzonitrile (VI), 1.246 kg (8.028 mol) of 2-cyanoethyl 3-oxobutanoate, 54.6 g (0.642 mol) of piperidine and 38.5 g (0.642 mol) of glacial acetic acid were heated under reflux in 10 1 of dichloromethane for 6.5 hours. The mixture was allowed to cool to room temperature and the organic phase was washed twice with 5 1 of water each time. The dichloromethane phase was then concentrated at atmospheric pressure, the still stirrable residue was dissolved in 15.47 kg of 2-butanol and 0.717 kg (5.78 mol) of 4-amino-5-methylpyridinone was added. The residual dichloromethane was distilled off until the internal temperature reached 98°C. The mixture was subsequently heated under reflux for 20 hours. The mixture was allowed to cool to 0°C, stirring was allowed to continue at this temperature for 4 hours and the product was filtered off. The product was dried under vacuum with entraining gas at 40°C.

[0368] Yield: 2.049 kg (87.6% of theory based on 4-amino-5-methylpyridinone, since this component was used in substoichiometric amounts) of a pale yellow solid.

[0369] HPLC Method A: RT about 9.7 min.

[0370] MS (EI pos): m / z = 405 [M+H] +

[0371] 1 H-NMR (300 MHz, DMSO-d6): δ = 2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H).

[0372] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxylic acid 2-cyanoethyl ester (XI)

[0373] To 6 1 of isopropanol are added 1.344 kg (8.34 mol) of 4-formyl-3-methoxybenzonitrile (VI), 71 g (0.834 mol) of piperidine and 50.1 g (0.834 mol) of glacial acetic acid and to this solution of 2-cyanoethyl 3-oxobutanoate in 670 ml of isopropanol is added at 30°C over a period of 3 h 1.747 kg (11.26 mol). The mixture is then stirred at 30°C for 1 h. The mixture is cooled to 0-3°C and stirred for 0.5 h. The product is filtered off and washed twice with 450 ml of cold isopropanol each time. For the determination of the yield, the product is dried in vacuo at 50°C (2.413 kg, 97% of theory); however, due to the high yield, the isopropanol-wetted product is usually directly further processed. For this purpose, the product is dissolved in 29 1 of isopropanol, 1.277 kg (7.92 mol) of 4-amino-5-methylpyridinone is added and the mixture is then heated to an internal temperature of 100°C in a closed vessel under a positive pressure of about 1.4 bar for 24 h. The mixture is then cooled to 0°C over a period of 5 h and stirred at 0°C for 3 h. The product is then filtered off and washed with 2.1 1 of cold isopropanol. The product is dried in vacuo at 60°C.

[0374] Yield: 2.819 kg (88% of theory based on 4-amino-5-methylpyridinone, since this component is used in substoichiometric amounts) of a pale yellow solid.

[0375] HPLC Method A: RT about 9.7 min.

[0376] MS (EI pos): m / z = 405 [M+H] +

[0377] 1 H-NMR (300 MHz, DMSO-d6): δ = 2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4.04 (m, 1 H), 4.11 (m, 1 H), 5.20 (s, 1 H), 6.95 (s, 1 H), 7.23 (dd, 1 H), 7.28-7.33 (m, 2H), 8.18 (s, 1 H), 10.76 (s, 1 H).

[0378] Example 5

[0379] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxylic acid 2-cyanoethyl ester (XI) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxylic acid 2-cyanoethyl ester (XI)

[0380] Dissolve 2.142 kg (5.3 mol) of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo- 1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid 2-cyanoethyl ester (X) and 4.70 kg (29 mol) of triethyl orthoacetate in 12.15 1 of dimethylacetamide and add 157.5 g of concentrated sulfuric acid. Heat the mixture at 115°C for 1.5 hours and then cool to 50°C. At 50°C, add 12.15 1 of water dropwise over 30 minutes. After the addition is complete, seed the mixture with 10 g of the title compound (XI) and add another 12.15 1 of water dropwise over 30 minutes at 50°C. Cool the mixture to 0°C (gradient, 2 hours) and stir at 0°C for 2 hours. Filter the product, wash twice with 7.7 1 of water each time and dry under vacuum at 50°C.

[0381] Yield: 2114.2 g (92.2% of theory) of a light yellow solid.

[0382] HPLC Method B: RT about 10.2 min.

[0383] MS (EI pos): m / z = 433 [M+H] +

[0384] 1 H-NMR (300 MHz, DMSO-d6): δ = 1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H).

[0385] Alternatively, the reaction can be carried out in NMP (1-methyl-2-pyrrolidone).

[0386] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxylic acid 2-cyanoethyl ester (XI) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxylic acid 2-cyanoethyl ester (XI)

[0387] Dissolve 2.142 kg (5.3 mol) of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo- 1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid 2-cyanoethyl ester (X) and 2.35 kg (14.5 mol) of triethyl orthoacetate in 3.21 kg of NMP (1 -methyl-2-pyrrolidone) and add 157.5 g of concentrated sulfuric acid. Heat the mixture at 115 °C for 1.5 hours and then cool to 50 °C. At 50 °C, add 2.2 1 of water dropwise over 30 minutes. After the addition is complete, add 10 g of the title compound (XI) as seed crystals to the mixture and add another 4.4 1 of water dropwise over 30 minutes at 50 °C. Cool the mixture to 0 °C (gradient, 2 hours) and then stir at 0 °C for 2 hours. Filter the product, wash twice with 4 1 of water each time and dry under vacuum at 50 °C.

[0388] Yield: 2180.7 g (95.1 % of theory) of a light yellow solid.

[0389] HPLC Method B: RT about 10.2 min.

[0390] Example 6

[0391] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxylic acid 2-cyanoethyl ester (XI) (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxamide (I) in acetonitrile / methanol 40:60

[0392] Dissolve 2.00 kg (4.624 mol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8- dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-cyanoethyl ester (XI) in a mixture of 12 1 of THF and 6 1 of water and cool to 0 °C. To this 0 °C solution, add an aqueous sodium hydroxide solution (prepared from 0.82 kg of a 45% aqueous NaOH solution (9.248 mol) and 4.23 1 of water) dropwise over 15 minutes and then stir the mixture at 0 °C for 1.5 hours. Extract the mixture twice with 4.8 1 of methyl tert-butyl ether each time and once with 4.8 1 of ethyl acetate. At 0 °C, adjust the aqueous solution to pH 7 with dilute hydrochloric acid (prepared from 0.371 kg of a 37% HCI and 1.51 of water). Allow the solution to warm to 20 °C and add 2.05 kg of an aqueous ammonium chloride solution in 5.54 1 of water. Stir the solution at 20 °C for 1 hour, filter the product, wash twice with 1.5 1 of water each time and once with 4 1 of acetonitrile. Dry the product under entraining gas at 40 °C.

[0393] Yield: 1736.9 g (99% of theory) of a nearly colourless powder (very light yellow).

[0394] HPLC Method C: RT: about 6.8 min.

[0395] MS (EIpos): m / z = 380 [M+H] +

[0396] 1 H-NMR (300 MHz, DMSO-d6): δ = 1.14 (t, 3H), 2.14 (s, 3H), 2.37 (s, 3H), 3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H).

[0397] Another work-up uses toluene for extraction:

[0398] (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxamide (I) Figure 1

[0399] Dissolve 2.00 kg (4.624 mol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8- dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-cyanoethyl ester (XI) in a mixture of 12 1 THF and 6 1 water and cool to 0°C. To this 0°C solution, add dropwise an aqueous sodium hydroxide solution (prepared from 0.82 kg of a 45% aqueous NaOH solution (9.248 mol) and 4.23 1 water) over 15 minutes and then stir the mixture at 0°C for 1.5 hours. Add 5 L of toluene and 381.3 g of sodium acetate and stir vigorously. Allow the phases to settle and separate the organic phase. Adjust the aqueous phase to pH 6.9 with 10% hydrochloric acid (seed the solution with 10 g of the title compound at about pH 9.5). Once the precipitation of the product is complete, stir the mixture at 0°C for 1 hour and then filter, washing twice with 4 1 of water each time and twice with 153 ml of toluene each time. Dry the product under vacuum at 40°C with entraining gas (nitrogen, 200 mbar). Yield: 1719.5 g (98% of theory) of almost colourless powder (very light yellow).

[0400] HPLC Method C: RT: about 6.8 min.

[0401] Example 7

[0402] Pharmaceutical formulation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4- dihydro-1,6-naphthyridine-3-carboxamide of formula (I) Figure 1

[0403] To 8 1 THF were added 1.60 kg (4.22 mol) 4-(4-cyano-2-methoxyphenyl)-5- ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (XII) and 958 g (5.91 mol) 1,1 -carbonyldiimidazole and at 20°C 51 g (0.417 mol) DMAP were added. The mixture was stirred at 20°C (gas evolution!) for 1 h and then heated to 50°C for 2.5 h. To this solution 2.973 kg (18.42 mol) hexamethyldisilazane were added and boiled under reflux for 22 h. Another 1.8 1 THF were added and the mixture was cooled to 5°C. A mixture of 1.17 1 THF and 835 g water was added within 3 h keeping the temperature between 5 and 20°C. Subsequently the mixture was boiled under reflux for 1 h and then cooled to 0°C by a gradient (3 h) and stirred at this temperature for 1 h. The product was filtered off, washed twice with 2.4 1 THF each and twice with 3.2 1 water each. The product was dried under vacuum at 70°C with entraining gas.

[0404] Yield: 1.501 kg (94% of theory) almost colourless powder (very light yellow).

[0405] HPLC Method B: RT about 6.7 min.

[0406] MS (EI pos): m / z = 379 [M+H] +

[0407] 1 H-NMR (300 MHz, DMSO-d6): δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

[0408] Example 8

[0409] Figure 2 Figure 3

[0410] Enantiomeric separation on an SMB system

[0411] The feed solution was a solution corresponding to a concentration consisting of 50 g of the racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- naphthyridine-3-carboxamide (XIII) dissolved in 1 1 of a mixture of methanol / acetonitrile 60:40.

[0412] The solution was chromatographically separated by an SMB system on a stationary phase: Chiralpak AS-V, 20 μm. The pressure was 30 bar and a mixture of methanol / acetonitrile 60:40 was used as eluent.

[0413] 9.00 kg of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- naphthyridine-3-carboxamide (XIII) were dissolved in 180 1 of a mixture consisting of methanol / acetonitrile 60:40 and chromatographically separated by an SMB. After concentration of the product containing fractions, 69.68 1 of a 6.2% solution (corresponding to 4.32 kg of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) in acetonitrile / methanol 40:60) were obtained.

[0414] Yield: 4.32 kg (48% of theory), colorless fractions dissolved in 69.68 1 of acetonitrile / methanol 40:60.

[0415] Enantiomeric purity: >98.5% e.e. (HPLC, method D)

[0416] The sample was concentrated under vacuum to give: MS (EI pos): m / z = 379 [M+H] +

[0417] 1 H-NMR (300 MHz, DMSO-d6): δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

[0418] Example 9

[0419] Figure 4 Figure 5

[0420] Crystallization and polymorph adjustment

[0421] The 64.52 L of a 6.2% solution in acetonitrile / methanol 40:60 mixture from example 8 (corresponding to 4.00 kg of compound 1) was filtered through a filter cartridge (1.2 μm) followed by concentration under 250 mbar until the solution was still stirrable. 48 I of ethanol denaturated with toluene were added and distilled again under 250 mbar until the stirrable limit (redistilled in ethanol). Another 48 I of ethanol denaturated with toluene were added and then distilled under atmospheric pressure until the total volume was reduced to about 14 I (jacket temperature 98 °C). The mixture was cooled through a gradient (4 hours) to 0 °C, stirred for 2 hours at 0 °C and the product was filtered off. The product was washed twice with 4 I of cold ethanol each and then dried under vacuum at 50 °C.

[0422] Yield: 3.64 kg (91% of theory) colorless crystalline powder.

[0423] Enantiomeric purity: > 99% e.e. (HPLC method D); Retention time / RRT: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- naphthyridine-3-carboxamide (I) about 11 min, RRT: 1.00; (4R)-4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxamide (I) about 9 min, RRT: 0.82

[0424] Purity: > 99.8% (HPLC method B), RT: about 6.7 min.

[0425] Content: 99.9% (relative to external standard)

[0426] Specific optical rotation (chloroform, 589 nm, 19.7 °C, c = 0.38600 g / 100 ml): -148.8°.

[0427] MS (EI pos): m / z = 379 [M+H] +

[0428] 1 H NMR (300 MHz, DMSO-d6): δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

[0429] Melting point: 252 °C (compound of formula (I) in crystalline form of polymorph I)

[0430] Physical-chemical characterization of the compound of formula (I) in crystalline form of polymorph I

[0431] The compound of formula (I) in crystalline form of polymorph I melts at 252°C with ΔH = 95-113 Jg -1 (heating rate 20 K min -1 , Figure 6 ).

[0432] A decrease in the melting point was observed, which depends on the heating rate.

[0433] At lower heating rates (e.g. 2 K min -1 ) the melting point decreases, since a decomposition occurs.

[0434] No other phase transition was observed. A mass loss of about 0.1 % was observed at temperatures up to 175°C.

[0435] Stability and hygroscopicity

[0436] A sample of the compound of formula (I) in crystalline form of polymorph I was stored at 85% and 97% relative humidity (25°C). The samples were evaluated by DSC, TGA and XRPD after 12 months. After 12 months a mass change of <0.1 % was observed in both cases. This means that the compound of formula (I) in crystalline form of polymorph I does not show a significant water uptake under these storage conditions. There is no difference according to DSC, TGA and XRPD for the compound of formula (I) in crystalline form of polymorph I.

[0437] Figure 7 Figure 8

[0438] A granulate solution of the compound of formula (I) in crystalline form of polymorph I, hypromellose 5 cP and sodium lauryl sulfate in purified water was prepared.

[0439] Microcrystalline cellulose, lactose monohydrate and croscarmellose sodium were mixed in a vessel or fluid bed granulator (premix).

[0440] The premix and the granulate solution were granulated in a fluid bed granulator.

[0441] The lubricant magnesium stearate was added, then the granulate was dried and sieved. A ready to press mixture was prepared thereby.

[0442] The ready to press mixture was tabletted with a rotary tablet press to give tablets.

[0443] A uniform coating suspension is prepared from hydroxypropyl methylcellulose, talc, titanium dioxide, yellow iron oxide, red iron oxide and purified water. The coating suspension is sprayed onto the tablets in a suitable coating apparatus.

[0444]

[0445]

[0446] HPLC conditions / methods

[0447] Method A

[0448] YMC Hydrosphere C18

[0449] 150 x 4.6 mm, 3.0 μm

[0450] 25°C, 1 ml / min, 270 nm, 4 nm

[0451] 0': 70% TFA 0.1%; 30% acetonitrile

[0452] 17': 20% TFA 0.1%; 80% acetonitrile

[0453] 18': 70% TFA 0.1%; 30% acetonitrile

[0454] *: TFA in water

[0455] Method B

[0456] YMC Hydrosphere C18

[0457] 150 x 4.6 mm, 3.0 μm

[0458] 25°C, 1 ml / min, 255 nm, 6 nm

[0459] 0': 90% TFA 0.1%; 10% acetonitrile

[0460] 20': 10% TFA 0.1%; 90% acetonitrile

[0461] 18': 10% TFA 0.1%; 90% acetonitrile

[0462] Method C

[0463] Nucleodur Gravity C18

[0464] 150 x 2 mm, 3.0 μm

[0465] 35 °C; 0.22 ml / min, 255 nm, 6 nm

[0466] Solution A: 0.58 g ammonium hydrogen phosphate and 0.66 g ammonium dihydrogen phosphate in 1 L water (ammonium phosphate buffer pH 7.2)

[0467] Solution B: acetonitrile

[0468] 0': 30% B; 70% A

[0469] 15': 80% B; 20% A

[0470] 25': 80% B; 20% A

[0471] Method D

[0472] Column length: 25 cm

[0473] Inner diameter: 4.6 mm

[0474] Filling: Chiralpak IA, 5 μm

[0475] Reagents: 1. Acetonitrile, HPLC grade

[0476] 2. Methyl tert-butyl ether (MTBE), p.a.

[0477] Test solution: The sample is dissolved in acetonitrile at a concentration of 1.0 mg / mL.

[0478] (e.g. about 25 mg sample, accurately weighed, dissolved in acetonitrile to 25.0 mL).

[0479] Eluent A. Acetonitrile

[0480] B. Methyl tert-butyl ether (MTBE), p.a.

[0481] Flow rate: 0.8 ml / min

[0482] Column oven temperature: 25 °C

[0483] Detection measurement wavelength: 255 nm

[0484] Bandwidth: 6 nm

[0485] Injection volume: 5 μL

[0486] Mixed composition of eluents A and B in a volume ratio of 90:10

[0487] Chromatography run time: 30 min

[0488] Retention time / RRT:

[0489] (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) ca. 11 min. RRT: 1.00

[0490] (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) ca. 9 min. RRT: 0.82

[0491] Lattice constants of the crystalline form of the compound of formula (I) in polymorph I

[0492] Polymorph I

[0493] Crystal system: orthorhombic

[0494] Space group: P2(1)2(1)2(1)

[0495] Number of molecules per unit cell: 4

[0496] Length of the a axis : 7.8610(3)

[0497] Length of the b axis : 11.7797(6)

[0498] Length of the c axis : 20.1792(8)

[0499] α [°]: 90

[0500] β [°]: 90

[0501] γ [°]: 90

[0502] Calculated density at 100 K [g cm -3 ]: 1.345

[0503] Measurement parameters for the x-ray diffraction method for measuring the crystalline form of the compound of formula (I) in polymorph I

[0504] Data set name 2429-08a r2

[0505] Scan axis 2 theta - omega

[0506] Start position [° 2 theta] 2.0000

[0507] End position [° 2 theta] 37.9900

[0508] Slit type Fixed

[0509] Slit size [°] 1.0000

[0510] Temperature of measurement [°C] 25

[0511] Anode material Cu

[0512] K-alpha 1 1.54060

[0513] Generator settings 35 mA, 45 kV

[0514] Diffractometer type Transmission diffractometer

[0515] Goniometer radius [mm] 240.00

[0516] Focusing-slit gap [mm] 91.00

[0517] Primary beam monochromator Yes

[0518] Sample rotation Yes

[0519]

[0520]

[0521]

[0522] Measurement conditions for IR and Raman spectroscopy for measuring the compound of formula (I) in crystalline form of polymorph I:

[0523] IR:

[0524] Instrument Perkin Elmer Spectrum One

[0525] Number of scans 32

[0526] Resolution 4 cm -1

[0527] Technique Diamond ATR unit

[0528] Raman:

[0529] Instrument Bruker Raman RFS 100 / S

[0530] Number of scans 64

[0531] Resolution 2-4 cm -1

[0532] Laser power 350 mW

[0533] Laser wavelength 1064 nm

[0534]

[0535] BRIEF DESCRIPTION OF DRAWINGS

[0536] Figure 9 DSC (20 K min-1) and TGA of the compound of formula (I) in crystalline form of polymorph I -1

[0537] Figure 10 Single crystal X-ray of polymorph I of (4S)-4-(4-cyano-2-methoxyphenyl)-5- ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3-carboxamide (1)

[0538] ​ X-ray diffractogram of the compound of formula (I) in crystalline form of polymorph I

[0539] ​ Raman spectrum of the compound of formula (I) in crystalline form of polymorph I

[0540] ​ FT-infrared (IR) spectrum (KBr) of the compound of formula (I) in crystalline form of polymorph I

[0541] ​ FT-infrared (IR) spectrum (ATR) of the compound of formula (I) in crystalline form of polymorph I

[0542] ​ FT-near-infrared (NIR) spectrum of the compound of formula (I) in crystalline form of polymorph I

[0543] ​ FT-far-infrared (FIR) spectrum of the compound of formula (I) in crystalline form of polymorph I

[0544] ​ Solid state NMR spectrum of the compound of formula (I) in crystalline form of polymorph I 13 C-NMR spectrum of the compound of formula (I) in crystalline form of polymorph I

[0545] ​ Stability of the compound of formula (I) in crystalline form of polymorph I under air humidity (x-axis: % relative humidity / y-axis: weight change in %)​

Claims

1. A process for the preparation of a compound of formula (I) comprising reacting a compound of formula (VI) with a compound of formula (VII) to give a compound of formula (VIIIa+b) reacting a compound of formula (VIII a+b) with a compound of formula (IX), to give a compound of formula (X), reacting a compound of formula (X) with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide under stirring at 100 to 120 °C for 1.5 to 3 hours to give a compound of formula (XI) saponifying a compound of formula (XI) with aqueous sodium hydroxide in a THF / water mixture to give a compound of formula (XII) reacting a compound of formula (XII) in a one-pot reaction first with carbonyldiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF, in a second step with hexamethyldisilazane under reflux for 16 to 24 hours and in a third step hydrolysis in water or water containing THF to give a compound of formula (XIII) in the presence of an enantiomeric mixture and isolating from the mixture a compound of formula (I).

2. The process according to claim 1, wherein a compound of formula (VI) is dissolved in isopropanol, 5-10 mole % piperidine and 5-10 mole % glacial acetic acid at 30 °C and the dissolved compound of formula (VI) is reacted with a compound of formula (VII), to give a compound of formula (VIIIa+b) 3. The process according to claim 1 or 2, wherein a compound of formula (VI) dissolved in 3-7 times isopropanol, 5-10 mole % piperidine and 5-10 mole % glacial acetic acid is reacted with a compound of formula (VII) at 30 °C to give a compound of formula (VIIIa+b).

4. The process according to claim 1 or 2, wherein a compound of formula (XI) is saponified with aqueous sodium hydroxide in 9 times THF / water 2:1 mixture to give a compound of formula (XII).

5. A process for the preparation of the compound of formula (I) in crystalline form of polymorph I, comprising the preparation of the compound of formula (I) in one or more polymorphic forms or solvates in an inert solvent according to the process of any one of claims 1 to 4, and stirring the compound of formula (I) in an inert solvent at a temperature of from 20 °C to 120 °C and isolating the compound of formula (I) in crystalline form of polymorph I, characterized in that, The polymorph I has peak maxima in the X-ray diffraction pattern measured by using a Cu K-alpha 1 radiation source at 2 theta angles of 8.5, 14.1, 17.2, 19.0, 20.5, 25.6, 26.

5.

6. The process for the preparation of a compound of formula (I) in the crystalline form of polymorph I according to claim 5, wherein the inert solvent is selected from the group consisting of methanol, ethanol, THF, propionitrile and mixtures thereof.

7. A process for the preparation of a medicament comprising preparing a compound of formula (I) in the crystalline form of polymorph I according to claim 5 or 6 and micronizing and formulating it into a medicament.

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