USRE49575E1 - Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient - Google Patents

Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient Download PDF

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USRE49575E1
USRE49575E1 US17/002,115 US201517002115A USRE49575E US RE49575 E1 USRE49575 E1 US RE49575E1 US 201517002115 A US201517002115 A US 201517002115A US RE49575 E USRE49575 E US RE49575E
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Johannes Platzek
Gunnar Garke
Alfons Grunenberg
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Bayer Pharma AG
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Definitions

  • the present invention relates to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)
  • the compound of the formula (I) acts as a non-steriodal antagonist of the mineralocorticoid receptor and may be used as an agent for prophylaxis and/or treatment of cardiovascular and renal disorders such as heart failure and diabetic nephropathy, for example.
  • Scheme 2 illustrates the novel process according to the invention, which affords the compound of the formula (I) in 9 stages in an overall yield of 27.7% of theory without chromatographic purification of intermediates.
  • methyl ester (XV) and the aldehyde (XVI) are not isolated but are further reacted directly in solution, which results in only 7 stages to be isolated.
  • a preparative chiral HPLC method e.g. SMB Technology, Varicol is used for the enantiomer separation.
  • the aldehyde (VI) is known from the literature (J. Med. Chem. 2007, 50, 2468-2485) and is an important intermediate in this synthesis. Meanwhile, there is also the possibility to purchase the compound commercially.
  • a dibromide (VIb) is prepared with NBS, which is reacted in ethanol with 2.46 eq. of silver nitrate (in water) to the target aldehyde (VI).
  • methyl ether ester (XV) is known from the literature (Journal of Medicinal Chemistry, 1992, vol. 35, p. 734-740) and is prepared by reaction with the highly volatile, harmful to health and expensive methyl iodide.
  • the toluene phase is separated and washed with water and saturated sodium chloride solution and the toluene solution subsequently distilled off to a certain volume (serves as azeotropic drying, i.e. removal of water for the subsequent stage). Determination of the solution content shows virtually complete conversion (>96% of theory).
  • the chlorine compound may be used analogously for which the achieved conversions are identical to the bromine compound.
  • the bromoaldehyde (XVI) is converted to the nitrile in a manner known per se by methods familiar to those skilled in the art (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), where in this case the nitrile aldehyde (VI) is obtained.
  • the ethyl acetate phase is separated off, the water phase washed again with ethyl acetate and the combined ethyl acetate phases then redistilled in isopropanol.
  • the product precipitates by water precipitation at the boiling temperature. After isolation, the product is dried under vacuum. In some cases, the product was precipitated directly by addition of water to the DMF and used directly in the subsequent stage after isolation and drying.
  • the reaction yields are generally >85% of theory. Palladium acetate is not adequate for the conversion of the chloro compound and it has proven advantageous in this case to use the palladium catalysts familiar to those skilled in the art, such as is described in Tetrahedron Lett. 48 (2007), 1087-1090, where the yields are somewhat lower than with the bromo compound, generally 80-85% of theory.
  • the cinnamic ester (VIII a,b) is obtained as an E/Z mixture starting from the aldehyde of the formula (VI) by a Knoevenagel reaction with the cyanoester (VIII):
  • the reaction proceeds preferably in boiling dichloromethane (10-fold) by addition of 5-20 mol % of piperidine, preferably 10 mol % and 5-20 mol % of glacial acetic acid, preferably 5-10 mol %, on a water separator.
  • the reaction time is 4-12 h, but preferably 5-6 h, particularly preferably 6 h.
  • 1.0-1.5 eq, preferably however 1.1 to 1.35 eq. or 1.25 eq to 1.35 eq of the cyanoester (VII) is added. With particular preference 1.1 eq. is added.
  • the preparation of the cyanoester (VII) is described in Pharmazie, 2000, vol. 55, p. 747-750 and Bioorg. Med. Chem.
  • reaction may be carried out, preferably in a secondary alcohol such as isopropanol, isobutanol, 2-amyl alcohol or cyclohexanol at temperatures of 80-160° C., at atmospheric pressure and also in autoclaves (2-10 bar), with reaction times of 8-40 h, but preferably for 20-25 h in boiling 2-butanol at atmospheric pressure or else in isopropanol in an autoclave (100° C., 2-10 bar, preferably 3-5 bar, 8-24 h).
  • a secondary alcohol such as isopropanol, isobutanol, 2-amyl alcohol or cyclohexanol
  • reaction times of 8-40 h, but preferably for 20-25 h in boiling 2-butanol at atmospheric pressure or else in isopropanol in an autoclave (100° C., 2-10 bar, preferably 3-5 bar, 8-24 h).
  • the mixture is cooled to 0° C. to 20° C., the crystals filtered off and
  • cyanoester (VII) cyanoester
  • VII cyanoester
  • the cinammic ester (VIIIa,b) crystallizes out during the reaction.
  • the product is subsequently filtered off, optionally after cooling, preferably at 0° C., washed with a little isopropanol (cooled to 0° C.) and used moist in the subsequent reaction as described above.
  • the yield is >96% of theory.
  • the subsequent reaction is preferably performed in 10-15 fold (with respect to aldehyde (VI)), preferably 11-12 fold isopropanol for 20-24 hours at 100° C. under pressure.
  • the product After termination of the reaction and cooling, the product is isolated by filtration or centrifugation. The product is subsequently dried at 40-90° C. under vacuum. Since the conversion to the cinammic ester proceeds virtually quantitatively, the process for the subsequent stage can be readily standardised without having to adjust the amount of heterocyle (IX) in each case, as the product can be used moist with isopropanol. The yields are >87% of theory.
  • the heterocycle (IX) can be prepared by known literature methods such as is described, for example, in Synthesis 1984, 765-766.
  • the ethyl ether (XI) is obtained by reaction under acidic catalysis with an orthoester, where R is —H or -methyl:
  • reaction can be carried out highly concentrated (up to 1.5 g of solvent per 1 g of reactant) in solvents such as dimethylacetamide, NMP (1-methyl-2-pyrrolidone) or DMF (dimethylformamide) by addition of 4-10% by weight, preferably 6-8% by weight, of conc. sulphuric acid.
  • solvents such as dimethylacetamide, NMP (1-methyl-2-pyrrolidone) or DMF (dimethylformamide)
  • solvents such as dimethylacetamide, NMP (1-methyl-2-pyrrolidone) or DMF (dimethylformamide)
  • the reaction is preferably carried out in DMA (dimethylacetamide) and/or NMP (1-methyl-2-pyrrolidone), at temperatures of 100-120° C., preferably 115° C.
  • DMA dimethylacetamide
  • NMP 1-methyl-2-pyrrolidone
  • it has proven advantageous to distill off some of the solvent (DMA and/or NMP) at elevated temperature (100-120° C. under vacuum) in order to remove any residues of isopropanol present from the precursor, as otherwise undesirable by-products occur.
  • Reaction Stir for 1.5-3 hours, preferably 2 hours.
  • water is added directly to the mixture, wherein the product crystallizes out. In order to have a particularly stable and reproducible process, a portion of the water (e.g.
  • the acid (XII) is obtained by alkaline saponification and subsequent acidic work-up.
  • the saponification was carried out at high dilution (33.9 fold) in a mixture of DME/water 3:1.
  • DME dimethyl methoxyethane
  • the reaction can also be conducted very readily highly concentrated in mixtures of THF/water.
  • the reaction is preferably performed in a mixture of THF/water 2:1 (9-fold), the aqueous sodium hydroxide solution is added at 0-5° C., then the mixture is stirred at 0-5° C. for 1-2 hours.
  • Aqueous potassium hydroxide can also be used but NaOH is preferably used.
  • the mixture is extracted with MTBE (methyl tert-butyl ether) and ethyl acetate and for the isolation the pH is adjusted with a mineral acid such as hydrochloric acid, sulphuric acid or phosphoric acid, but preferably hydrochloric acid, to pH 6.5-7.0 or pH 7.
  • the mixture is then mixed with saturated ammonium salt solution of the corresponding acid, but preferably ammonium chloride solution, wherein the product quantitatively crystallizes out.
  • the subsequent conversion of the acid to the amide (XIII) was carried out in the research stage as follows:
  • the acid (XII) was dissolved in ca. 10-fold DMF, 1.25 eq. of 1,1′-carbodiimidazole and 0.1 eq. of DMAP (4-(dimethylamino)pyridine) were added and the mixture was stirred at room temperature for 4 hours.
  • DMAP dimethylamino
  • 20 eq. of ammonia in the form of an aqueous 25% solution were added and this mixture transferred to an oilbath pre-heated to 110° C.
  • relatively large amounts of ammonia gas form instantaneously, which escape the system and in addition ensure a sharp increase in pressure.
  • This mixture was added to ca.
  • the amide (XIII) crystallises out directly from the solution and can be obtained in high yield and purity.
  • the carboxylic acid (XII) in THF is reacted with 1.1 to 1.6 eq., preferably 1.3-1.4 eq. of 1,1′-carbodiimidazole under DMAP catalysis (5-15 mol %, preferably 10 mol %) to give the imidazolide, which takes place at temperatures between 20-50° C., the preferred approach having proven to be initially starting at 20° C., then stirring 1 to 2 hours at this temperature and then further stirring at 50° C. for 2 to 3 hours.
  • the mixture is boiled under reflux for 16-24 hours, but preferably 16 hours.
  • the resulting disilylamide compound here can optionally be isolated but it has been proven to be advantageous to continue in a one-pot reaction. Therefore, on completion of the reaction, the mixture is cooled to 0-3° C. and a mixture of water/or in a mixture with THF is added, it having proven to be advantageous to use an amount of water of 0.5 to 0.7 fold (with respect to reactant), particularly advantageous being an amount of water of 0.52 fold.
  • the water can be added directly or as a mixture with approximately an equivalent up to double the amount of THF by volume.
  • the mixture is heated under reflux for 1-3 hours in total, preferably 1 hour.
  • the mixture is cooled to 0° C. and stirred for 1-5 hours, preferably 3 hours, at this temperature, 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 at 60° C. to 90° C. or at 40° C. to 70° C.).
  • the yields are very high and are generally >93% of theory.
  • the purity is generally >99% (HPLC, 100% method).
  • the compound (XIII) may also be obtained directly by reacting with ammonia gas in the autoclave (ca. 25 to 30 bar).
  • the preactivation described above is carried out and the reaction mixture is heated under pressure under gaseous ammonia. On completion of the reaction, it is cooled and the product filtered off.
  • the yields and purities thus achieved are comparable.
  • the racemic mixture of amides (XIII) must be separated into the antipodes.
  • a specifically synthesized chiral phase was used for this purpose (prepared in-house), which comprised N-(dicyclopropylmethyl)-N 2 -methacryloyl-D-leucinamide as chiral selector.
  • This selector was prepared in a multi-stage process and then polymerized on special silica gel. Methanol/ethyl acetate served as eluent.
  • a major disadvantage of this method was the very low loading, 30 mg per separation on a 500*63 mm chromatography column, such that there was a high need to find as effective a separation method as possible which allows separation of antipodes to be performed in the multi-tonne range. It has been found, surprisingly, that the separation can be performed on a readily commercially available phase. This takes the form of the phase Chiralpak AS-V, 20 ⁇ m.
  • the eluent used was a mixture of methanol/acetonitrile 60:40. This mixture has the major advantage that it can be recovered as eluent after distillative work-up having the identical composition (60:40 corresponds to the azeotrope.
  • the yield of the separation is >47% of theory (50% is theoretically possible).
  • the optical purity here is >93% e.e. but preferably >98.5% e.e.
  • the chromatography may be carried out on a conventional chromatography column, but preferably the techniques known to those skilled in the art such as SMB or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901) are used.
  • SMB Seros Management System
  • Varicol Computer Engineering 27 (2003) 1883-1901
  • ca. 500 kg of the racemic amide (XIII) was separated using an SMB system, in which a yield of 48% was achieved.
  • the product is obtained as a 3-8%, preferably 5-7% solution in a mixture of methanol/acetonitrile 60:40 and can be used directly in “final processing”.
  • solvent mixture ratios of acetonitrile to methanol are also conceivable (90:10 to 10:90).
  • other solvent mixtures can also be used, however, for the SMB separation, such as acetonitrile/ethanol in mixture ratios of 10:90 to 90:10.
  • the particular solvent ratio depends partly on the technical properties of the SMB system and must be adjusted, if appropriate (e.g. varying flow rate, recycling of the solvent on a thin film evaporator).
  • the compound of the formula (I) has been developed in the form of a tablet, there exists a high demand that the isolated compound of the formula (I) is isolated in a defined crystalline form in a reproducible manner such that a reproducible bioavailability can be ensured. It has been found, surprisingly, that the compound of the formula (I) can be crystallized from methanol, ethanol, THF, acetonitrile, and also mixtures thereof with water, wherein only one polymorph I is reproducibly formed, which has a defined melting point of 252° C. By way of advantage, ethanol or denatured ethanol is used.
  • the ca. 5-7% product solution in methanol/acetonitrile 60:40 (or, if ethanol/acetonitrile was employed, a ca. 3-4% solution of ethanol/acetonitrile 50:50) originating from the chromatography is firstly subjected to a particle filtration for GMP technical reasons and subsequently a solvent exchange with ethanol is performed, preferably using ethanol denatured with toluene.
  • the solution is repeatedly redistilled, concentrated and fresh ethanol added each time. After exchange, as much ethanol is added until a solution phase is passed through at the boiling point and then it is concentrated under atmospheric pressure or under slightly reduced pressure to ca.
  • the present invention provides the compound of the formula (I) in crystalline form of polymorph I
  • the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 8.5, 14.1, 17.2, 19.0, 20.5, 25.6, 26.5.
  • the present invention further provides the compound of the formula (I) in crystalline form of polymorph I
  • IR-ATR IR-ATR
  • the present invention further provides the compound of the formula (I) in crystalline form of polymorph I
  • the Raman spectrum of the compound exhibits band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827 and 155 cm ⁇ 1 .
  • the present invention further provides a process for preparing the compound of the formula (I) in crystalline form of polymorph I, characterized in that the compound of the formula (I), present in one or more polymorphs or as a solvate in an inert solvent, is stirred at a temperature of 20° C.-120° C. and the compound of the formula (I) is isolated in crystalline polymorph I.
  • Preferred solvents for the process for preparing the compound of the formula (I) in crystalline form of polymorph I are methanol, ethanol, THF, acetonitrile, and also mixtures thereof. Particular preference is given to ethanol or denatured ethanol.
  • a preferred temperature range for the process for preparing the compound of the formula (I) in crystalline form of polymorph I is from 20° C. to 90° C.
  • the present invention further provides a compound of the formula (I) in crystalline form of polymorph (I) as described above for treatment of disorders.
  • the present invention further provides a medicament comprising a compound of the formula (I) in crystalline form of polymorph (I) as described above and no greater proportions of any other form of the compound of the formula (I) in crystalline form of polymorph (I) as described above.
  • the present invention further provides a medicament comprising a compound of the formula (I) in crystalline form of polymorph (I) as described above in more than 90 percent by weight based on the total amount of the compound of the formula (I) present in crystalline form of polymorph (I) as described above.
  • the present invention further provides for the use of the compound of the formula (I) in crystalline form of polymorph I as described above. To prepare a medicament for the treatment of cardiovascular disorders.
  • the present invention further provides the method for treatment of cardiovascular disorders by administering an effective amount of a compound of the formula (I) in crystalline form of polymorph (I) as described above.
  • the present invention further provides a process for preparing compound (I), characterized in that the compound of the formula (XIV) or the formula (XIVa)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (VI)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (X)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (XI)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (XII)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (XIV) or the formula (XIVa)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (VI)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (X)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (XI)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (XIV) or the formula (XIVa)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (VI)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (X)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (XIV) or the formula (XIVa)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (VI)
  • the present invention further provides a process for preparing compound of the formula (I), characterized in that the compound of the formula (XIV) or the formula (XIVa)
  • the crystallization process is very robust and affords the compound of the formula I in crystalline form of polymorph I in a reproducible manner (m.p. 252° C.). Surprisingly, it is also possible to use material with lower optical purities in the crystallization process and it was shown that even a material of 93% e.e. still gives rise after crystallization to >99% e.e.
  • the compound of the formula (I) is generally micronized and to be formulated into the pharmaceutical. It is found that the compound of the formula (I) in crystalline form of polymorph I has very good stability properties (even at high atmospheric humidity) and can be stored without any problem for >2 years.
  • the compounds according to the invention act as antagonists of the mineralocorticoid receptor and exhibit an unforeseeable, useful spectrum of pharmacological activity. They are therefore suitable for use as medicaments for treatment and/or prophylaxis of disorders in humans and animals.
  • inventive compounds are suitable for the prophylaxis and/or treatment of various disorders and disease-related conditions, especially of disorders characterized either by an increase in the aldosterone concentration in the plasma or by a change in the aldosterone plasma concentration relative to the renin plasma concentration, or associated with these changes.
  • disorders characterized either by an increase in the aldosterone concentration in the plasma or by a change in the aldosterone plasma concentration relative to the renin plasma concentration, or associated with these changes.
  • Examples include: idiopathic primary hyperaldosteronism, hyperaldosteronism associated with adrenal hyperplasia, adrenal adenomas and/or adrenal carcinomas, hyperaldosteronism associated with cirrhosis of the liver, hyperaldosteronism associated with heart failure, and (relative) hyperaldosteronism associated with essential hypertension.
  • inventive compounds are also suitable, because of their mechanism of action, for the prophylaxis of sudden cardiac death in patients at increased risk of dying of sudden cardiac death.
  • these are patients who suffer, for example, from any of the folllowing 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 ischaemia, myocardial infarction, dilative cardiomyopathies, inherited primary cardiomyopathies, for example Brugada syndrome, cardiomyopathies caused by Chagas disease, shock, arteriosclerosis, atrial and ventricular arrhythmia, transient and ischaemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and cardiac vascular disorders, peripheral blood flow disturbances, arterial occlusive disorders such as intermittent claudication, asymptomatic left-ventricular dysfunction, myocarditis, hypertrophic changes to the heart, pulmonary hypertension, spasms of the coronary arteries
  • inventive compounds can also be used for the prophylaxis and/or treatment of edema formation, for example pulmonary oedema, renal oedema or heart failure-related oedema, and of restenoses such as following thrombolysis therapies, percutaneous transluminal angioplasties (PTA) and percutaneous transluminal coronary angioplasties (PTCA), heart transplants and bypass operations.
  • thrombolysis therapies percutaneous transluminal angioplasties (PTA) and percutaneous transluminal coronary angioplasties (PTCA), heart transplants and bypass operations.
  • PTA percutaneous transluminal angioplasties
  • PTCA percutaneous transluminal coronary angioplasties
  • inventive compounds are further suitable for use as a potassium-saving diuretic and for electrolyte disturbances, for example hypercalcaemia, hypernatraemia or hypokalaemia.
  • inventive compounds are equally suitable for treatment of renal disorders, such as acute and chronic renal failure, hypertensive renal disease, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal insufficiency and cystic renal disorders, for prevention of renal damage which can be caused, for example, by immunosuppressives such as cyclosporin A in the case of organ transplants, and for renal cancer.
  • renal disorders such as acute and chronic renal failure, hypertensive renal disease, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal insufficiency and cystic renal disorders
  • immunosuppressives such as cyclosporin A in the case of organ transplants, and for renal cancer.
  • inventive compounds can additionally be used for the prophylaxis and/or treatment of diabetes mellitus and diabetic sequelae, for example neuropathy and nephropathy.
  • inventive compounds can also be used for the prophylaxis and/or treatment of microalbuminuria, for example caused by diabetes mellitus or high blood pressure, and of proteinuria.
  • inventive compounds are also suitable for the prophylaxis and/or treatment of disorders associated either with an increase in the plasma glucocorticoid concentration or with a local increase in the concentration of glucocorticoids in tissue (e.g. of the heart).
  • disorders associated either with an increase in the plasma glucocorticoid concentration or with a local increase in the concentration of glucocorticoids in tissue (e.g. of the heart).
  • Examples include: adrenal dysfunctions leading to overproduction of glucocorticoids (Cushing's syndrome), adrenocortical tumours with resulting overproduction of glucocorticoids, and pituitary tumours which autonomously produce ACTH (adrenocorticotropic hormone) and thus lead to adrenal hyperplasias with resulting Cushing's disease.
  • ACTH adrenocorticotropic hormone
  • inventive compounds can additionally be used for the prophylaxis and/or treatment of obesity, of metabolic syndrome and of obstructive sleep apnoea.
  • inventive compounds can also be used for the prophylaxis and/or treatment of inflammatory disorders caused for example by viruses, spirochetes, fungi, bacteria or mycobacteria, and of inflammatory disorders of unknown etiology, such as polyarthritis, lupus erythematosus, peri- or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • inflammatory disorders caused for example by viruses, spirochetes, fungi, bacteria or mycobacteria
  • inflammatory disorders of unknown etiology such as polyarthritis, lupus erythematosus, peri- or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • inventive compounds can further be employed for the treatment of central nervous disorders such as depression, states of anxiety and chronic pain, especially migraine, and for neurodegenerative disorders such as Alzheimer's disease and Parkinson's syndrome.
  • central nervous disorders such as depression, states of anxiety and chronic pain, especially migraine
  • neurodegenerative disorders such as Alzheimer's disease and Parkinson's syndrome.
  • inventive compounds are also suitable for the prophylaxis and/or treatment of vascular damage, for example following procedures such as percutaneous transluminal coronary angioplasty (PTCA), implantation of stents, coronary angioscopy, reocclusion or restenosis following bypass operations, and for endothelial dysfunction, for Raynaud's disease, for thromboangiitis obliterans (Buerger' s syndrome) and for tinnitus syndrome.
  • PTCA percutaneous transluminal coronary angioplasty
  • stents implantation of stents
  • coronary angioscopy reocclusion or restenosis following bypass operations
  • endothelial dysfunction for Raynaud's disease
  • thromboangiitis obliterans Buserger' s syndrome
  • tinnitus syndrome for tinnitus syndrome.
  • the present invention further provides for the use of the compounds according to the invention for treatment and/or prevention of disorders, especially the aforementioned disorders.
  • the present invention further provides for the use of the compounds according to the invention for producing a medicament for the treatment and/or prevention of disorders, in particular the disorders mentioned above.
  • the present invention further provides a process for treatment and/or prevention of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
  • the compounds according to the invention can be used alone or, if required, in combination with other active compounds.
  • the present invention furthermore provides medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for treatment and/or prevention of the abovementioned disorders.
  • Preferred examples of active compounds suitable for combinations include:
  • the compounds according to the invention are administered in combination with a diuretic, by way of example and with preference furosemide, bumetanide, torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic by way of example and with preference furosemide, bumetanide, torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone
  • Agents which lower blood pressure are preferably understood to mean compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, Rho kinase inhibitors, and the diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.
  • the inventive compounds are administered in combination with an angiotensin AII antagonist, preferred examples being losartan, candesartan, valsartan, telmisartan or embusartan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor, by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist, by way of example and with preference bosentan, darusentan, ambrisentan or sitaxsentan.
  • the inventive compounds are administered in combination with a renin inhibitor, preferred examples being aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, by way of example and with preference prazosin.
  • the compounds according to the invention are administered in combination with a beta-receptor blocker, by way of example and with preference 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.
  • a beta-receptor blocker by way of example and with preference propranolol, atenolol, timolol, pindo
  • the compounds according to the invention are administered in combination with a rho kinase inhibitor, by way of example and with preference fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.
  • a rho kinase inhibitor by way of example and with preference fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.
  • Antithrombotic agents are preferably understood to mean compounds from the group of platelet aggregation inhibitors, of anticoagulants or of profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, by way of example and with preference aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor by way of example and with preference aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, by way of example and with preference ximelagatran, melagatran, bivalirudin or clexane.
  • the compounds according to the invention are administered in combination with a GPIIb/IIIa antagonist, by way of example and with preference tirofiban or abciximab.
  • the compounds according to the invention are administered in combination with a factor Xa inhibitor, by way of example and with preference 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.
  • a factor Xa inhibitor by way of example and with preference rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-10
  • the compounds according to the invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, by way of example and with preference coumarin.
  • Lipid metabolism modifiers are preferably understood to mean compounds from the group of the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein(a) antagonists.
  • the CETP inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-gamma and/or PPAR-delta agonists
  • cholesterol absorption inhibitors polymeric bile acid
  • the compounds according to the invention are administered in combination with a CETP inhibitor, by way of example and with preference torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant).
  • a CETP inhibitor by way of example and with preference torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist, by way of example and with preference D-thyroxin, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist by way of example and with preference D-thyroxin, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • an HMG-CoA reductase inhibitor from the class of statins, by way of example and with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, by way of example and with preference BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor, by way of example and with preference implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, by way of example and with preference pioglitazone or rosiglitazone.
  • the inventive compounds are administered in combination with a PPAR-delta agonist, preferred examples being GW-501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, by way of example and with preference ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, by way of example and with preference orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, by way of example and with preference cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • the compounds according to the invention are administered in combination with a lipoprotein(a) antagonist, by way of example and with preference gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein(a) antagonist by way of example and with preference gemcabene calcium (CI-1027) or nicotinic acid.
  • the present invention further provides medicaments which comprise at least one compound according to the invention, typically together with one or more inert, non-toxic, pharmaceutically suitable excipients, and the use thereof for the aforementioned purposes.
  • the compounds according to the invention can act systemically and/or locally.
  • they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms for these administration routes.
  • Suitable administration forms for oral administration are those which work according to the prior art and release the compounds according to the invention rapidly and/or in a modified manner and which contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the compound according to the invention), tablets or films/oblates which disintegrate rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the compound according to the invention
  • tablets or films/oblates which disintegrate rapidly in the oral cavity
  • films/lyophilizates for example hard or soft gelatin capsules
  • Parenteral administration can be accomplished with avoidance of a resorption step (for example by an intravenous, intraarterial, intracardiac, intraspinal or intralumbar route) or with inclusion of a resorption (for example by an intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal route).
  • Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • suitable examples are inhalable medicament forms (including powder inhalers, nebulizers), nasal 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 (e.g. patches), milk, pastes, foams, sprinkling powders, implants or stents.
  • Oral and parenteral administration are preferred, especially oral and intravenous administration.
  • the compounds according to the invention can be converted to the administration forms mentioned. This can be accomplished in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), colorants (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour correctants.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium do
  • parenteral administration amounts 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.
  • the dosage is 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.
  • the mixture is then stirred at 0° C. for 1.5 hours.
  • the solution is added to cold aqueous sulphuric acid at 0° C. (12.5 l of water+1.4 kg of conc. sulphuric acid). The temperature should increase at maximum to 10° C. (slow addition).
  • the pH is adjusted to pH 1, if necessary, by addition of further sulphuric acid.
  • the organic phase is separated off and the aqueous phase is extracted with 7.61 of toluene.
  • the combined organic phases are washed with 5.1 l of water and then substantially concentrated and the residue taken up in 10 l of DMF.
  • the solution is again concentrated to a volume of ca. 5 l. Determination of the content by evaporation of a portion results in a converted yield of 1.041 kg (94.1% of theory).
  • the solution is used directly in the subsequent stage.
  • the mixture is extracted with 17 l of ethyl acetate and the aqueous phase washed once more with 17 l of ethyl acetate.
  • the organic phases are combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to ca. 2 l.
  • the mixture is heated to boiling and 2 l of water added dropwise.
  • the mixture is allowed to cool to 50° C. and 2 l of water added anew.
  • the mixture is cooled to 3° C. and stirred at this temperature for one hour.
  • the product is filtered off and washed with water (2 times 1.2 l).
  • the product is dried at 40° C. under vacuum.
  • the dichloromethane phase is then concentrated at atmospheric pressure and the still stirrable residue is taken up in 15.47 kg of 2-butanol and 0.717 kg (5.78 mol) of 4-amino-5-methylpyridone is added.
  • the residual dichloromethane is distilled off until an internal temperature of 98° C. is reached.
  • the mixture is subsequently heated under reflux for 20 hours.
  • the mixture is cooled to 0° C., allowed to stir at this temperature for 4 hours and the product is filtered off.
  • the product is dried at 40° C. under vacuum under entraining gas.
  • the product is dried at 50° C. under vacuum (2.413 kg, 97% of theory); however, due to the high yield, the isopropanol-moist product is generally further processed directly.
  • the product is taken up in 29 l of isopropanol and 1.277 kg (7.92 mol) of 4-amino-5-methylpyridone are added and then the mixture is heated to an internal temperature of 100° C. under a positive pressure of ca. 1.4 bar for 24 h in a closed vessel.
  • the mixture is then cooled to 0° C. by means of a gradient over a period of 5 h and then stirred at 0° C. for 3 hours.
  • the product is then filtered off and washed with 2.1 l of cold isopropanol.
  • the product is dried at 60° C. under vacuum.
  • the mixture is seeded with 10 g of the title compound (XI) and a further 12.15 l of water are added dropwise over 30 minutes at 50° C.
  • the mixture is cooled to 0° C. (gradient, 2 hours) and stirred at 0° C. for two hours.
  • the product is filtered off, washed twice with 7.7 l each time of water and dried at 50° C. under vacuum.
  • reaction may be carried out in NMP (1-methyl-2-pyrrolidone)
  • the mixture is seeded with 10 g of the title compound (XI) and a further 4.4 l of water are added dropwise over 30 minutes at 50° C.
  • the mixture is cooled to 0° C. (gradient, 2 hours) and then stirred at 0° C. for two hours.
  • the product is filtered off, washed twice with 4 l each time of water and dried at 50° C. under vacuum.
  • the mixture is extracted twice with 4.8 l of methyl tert-butyl ether each time and once with 4.8 l of ethyl acetate.
  • the aqueous solution at 0° C. is adjusted to pH 7 with dilute hydrochloric acid (prepared from 0.371 kg of 37% HCl and 1.51 l of water).
  • the solution is allowed to warm to 20° C. and an aqueous solution of 2.05 kg of ammonium chloride in 5.54 l of water is added.
  • the solution is stirred at 20° C. for 1 hour, the product filtered and washed twice with 1.5 l of water each time and once with 4 l of acetonitrile.
  • the product is dried at 40° C. under entraining gas.
  • a further 1.8 l of THF is added and the mixture cooled to 5° C.
  • a mixture of 1.17 l of THF and 835 g of water is added over 3 hours such that the temperature remains between 5 and 20° C.
  • the mixture is subsequently boiled under relux for one hour, then cooled via a gradient (3 hours) to 0° C. and stirred at this temperature for one hour.
  • the product is filtered off and washed twice with 2.4 l of THF each time and twice with 3.2 l of water each time.
  • the product is dried at 70° C. under vacuum under entraining gas.
  • the feed solution is a solution corresponding to a concentration consisting of 50 g of racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII), dissolved in 1 liter of a mixture of methanol/acetonitrile 60:40.
  • the solution is chromatographed by means of an SMB system on a stationary phase: Chiralpak AS-V, 20 ⁇ m.
  • the pressure is 30 bar and a mixture of methanol/acetonitrile 60:40 is used as eluent.
  • the mixture was cooled via a gradient (4 hours) to 0° C., stirred at 0° C. for 2 hours and the product filtered off.
  • the product was washed twice with 4 l of cold ethanol each time and then dried at 50° C. under vacuum.
  • the melting point decreases at a lower heating rate (e.g. 2 Kmin ⁇ 1 ) since decomposition occurs.
  • a granular solution of the compound of the formula (I) in crystalline form of polymorph I in micronized form, hypromellose 5 cP and sodium lauryl sulphate was prepared in purified water.
  • Microcrystalline cellulose, lactose monohydrate and croscarmellose sodium were mixed (premix) in a container or a fluidized bed granulator.
  • the premix and the granular solution were granulated in the fluid-bed granulator.
  • the lubricant magnesium stearate was added after which the granulate was dried and sieved. A ready to press mixture was thus prepared.
  • the ready to press mixture was compressed to give tablets using a rotary tablet press.
  • a homogeneous coating suspension was prepared from hypromellose, talc, titanium dioxide, yellow iron oxide, red iron oxide and purified water. The coating suspension was sprayed onto the tablets in a suitable coating device.
  • Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Composition [mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg] Compound 1.25 2.50 5.00 7.50 10.00 15.00 20.00 of the formula (I) in polymorph I micronized Excipients Microcrystalline 73.80 72.50 69.90 67.30 64.70 62.00 59.30 cellulose Croscarmellose 4.50 4.50 4.50 4.50 4.50 4.50 4.50 sodium Hypromellose 5 cP 4.50 4.50 4.50 4.50 4.50 4.50 4.50 4.50 4.50 4.50 Lactose monohydrate 45.00 45.00 45.00 45.00 42.50 40.00 Magnesium stearate 0.90 0.90 0.90 0.90 0.90 0.90 Sodium lauryl 0.05 0.10 0.20 0.30 0.40 0.60 0.80 sulphate Weight (uncoated 130.00 130.00 130.00 13
  • Solution A 0.58 g of ammonium hydrogen phosphate and 0.66 g of ammonium dihydrogen
  • Test solution The sample is dissolved at a concentration of 1.0 mg/mL
  • FIG. 1 DSC (20 Kmin ⁇ 1 ) and TGA of compound of the formula (I) in crystalline form of polymorph I
  • FIG. 2 X-ray of a single crystal of polymorph I of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1)
  • FIG. 3 X-ray diffractogram of compound of the formula (I) in crystalline form of polymorph I
  • FIG. 4 Raman spectrum of compound of the formula (I) in crystalline form of polymorph I
  • FIG. 5 FT-Infrared (IR) spectrum (KBr) of compound of the formula (I) in crystalline form of polymorph I
  • FIG. 6 FT-Infrared (IR) spectrum (ATR) of compound of the formula (I) in crystalline form of polymorph I
  • FIG. 7 FT-Near-infrared (NIR) spectrum of compound of the formula (I) in crystalline form of polymorph I
  • FIG. 8 FT-Far-infrared (FIR) spectrum of compound of the formula (I) in crystalline form of polymorph I
  • FIG. 9 Solid state 13 C-NMR spectrum of compound of the formula (I) in crystalline form of polymorph I
  • FIG. 10 Stability of compound of the formula (I) in crystalline form of polymorph I in air humidity (x-axis % relative humidity/y-axis weight change in %

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US17/002,115 2014-08-01 2015-07-29 Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient Active USRE49575E1 (en)

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