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EP3337799A1 - Procédé de préparation de métabolites de (4s) et (4r)- 4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide et leur utilisation - Google Patents

Procédé de préparation de métabolites de (4s) et (4r)- 4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide et leur utilisation

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Publication number
EP3337799A1
EP3337799A1 EP16750868.8A EP16750868A EP3337799A1 EP 3337799 A1 EP3337799 A1 EP 3337799A1 EP 16750868 A EP16750868 A EP 16750868A EP 3337799 A1 EP3337799 A1 EP 3337799A1
Authority
EP
European Patent Office
Prior art keywords
compound
metabolites
rac
formula
naphthyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16750868.8A
Other languages
German (de)
English (en)
Inventor
Johannes Platzek
Ludwig Zorn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP3337799A1 publication Critical patent/EP3337799A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

  • the present invention relates to a novel process for the preparation of (4R) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxamide of the formula 4R (I) and the metabolites of (4S) - and (4R) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1, 6-naphthyridine-3-carboxamide of the formula (I), of the formulas Mla (S), Mlb (R), M2a (S), M2b (R), M3a (S), M3b (R) and their use.
  • the compound of formula 4S (I) acts as a non-steroidal antagonist of the mineralcorticoid receptor and can be used as an agent for the prophylaxis and / or treatment of cardiovascular and renal diseases such as heart failure and chronic kidney disease.
  • the oxidizing agents which can be used are those which are familiar to the person skilled in the art for the aromatization of piperidines and dihydropyridines; these are shown by way of example in the book Pyridines: From Lab to Production; Edited by Eric F.V. Scriven, Elsevier Verlag 2013, chapter 8, pages 116-144.
  • Examples include DDQ in dichloromethane, chloranil in dichloromethane, manganese dioxide in dichloromethane, potassium permanganate in acetone, manganese (III) acetate in glacial acetic acid, cerium ammonium acetate in acetonitrile, pyridinium chlorochromate in dichloromethane, conc.
  • Nitric acid in dichloromethane The yields are generally very high, usually> 86% of theory.
  • rac M2 obtained by a selective hydroxylation of the methyl group. This is achieved using Cyp-P450 expressed in E. coli, eg E. coli JM109 P450 3A4 was obtained from Oxford Biomedical Research (reactions are described in: SP Hanion, T. Friedberg, CR Wolf, O. Ghisalba, M Kittelmann in Modern Biooxidation: Enzymes, Reactions and Applications (Eds .: RD Schmid, VB Urlacher), Wiley-VCH, Weinheim, 2007, pp. 233-252, JAR Blake, M. Pritchard, S. Ding, GCM Smith, Burchell, CR Wolf, T. Friedberg, FEBS Lett., 1996, 397, 210-214; A.
  • the racemic mixture of rac Ml in Mla and Mlb, the racemic mixture of rac M2 in M2a and M2b and the racemic mixture of rac M3 in M3a and M3b are separated by chromatography on a chiral phase.
  • 4R (I) mainly consists of the b-series metabolites, ie Mlb (R), M2b (R) and M3b (R). Absolute configuration was determined by X-ray diffraction and CD spectroscopy (see examples).
  • the metabolites are a few orders of magnitude weaker in their pharmacological activity than the compound of formula (I).
  • the compound of formula (I) and its metabolites act as antagonists of the mineralocorticoid receptor and do not show one predictable, valuable pharmacological spectrum of action. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compound of formula (I) and its metabolites are useful for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular diseases related to either by an increase in plasma aldosterone concentration or by a change in plasma aldosterone concentration labeled with the renin plasma concentration or are associated with these changes.
  • diseases related to either by an increase in plasma aldosterone concentration or by a change in plasma aldosterone concentration labeled with the renin plasma concentration or are associated with these changes.
  • examples include: idiopathic primary hyperaldosteronism, hyperaldosteronism in adrenal hyperplasia,
  • the compound (I) and its metabolites are also suitable for the prevention of sudden cardiac death in patients who are at increased risk of dying from sudden cardiac death because of their mechanism of action.
  • patients e.g. suffer from any of the following conditions: 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, dilated cardiomyopathies, congenital primary cardiomyopathies, e.g.
  • Brugada syndrome cardiomyopathies caused by Chagas' disease, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral circulatory disorders, arterial occlusive diseases such as intermittent claudication, asymptomatic left ventricular Dysfunction, myocarditis, hypertrophic changes of the heart, pulmonary hypertension, spasm of the coronary arteries and peripheral arteries, thrombosis, thromboembolic disorders and vasculitis.
  • Compound (I) and its metabolites may also be used for the prophylaxis and / or treatment of edema formation, such as pulmonary edema, renal edema or heart failure-related edema, and restenosis, such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA ) and coronary angioplasties (PTCA), heart transplants and bypass surgery.
  • edema formation such as pulmonary edema, renal edema or heart failure-related edema
  • restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA ) and coronary angioplasties (PTCA), heart transplants and bypass surgery.
  • PTA percutaneous transluminal angioplasty
  • PTCA coronary angioplasties
  • the compound (I) and its metabolites are suitable for use as a potassium-sparing diuretic and in electrolyte disorders such as hypercalcaemia, hypernatremia or hypocalcaemia.
  • Compound (I) and its metabolites are also useful in the treatment of renal diseases such as acute and chronic renal failure, hypertensive renal disease, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal insufficiency and cystic Kidney disease, to prevent kidney damage caused by, for example, immunosuppressants such as cyclosporin A in organ transplants, as well as kidney cancer.
  • renal diseases such as acute and chronic renal failure, hypertensive renal disease, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal insufficiency and cystic Kidney disease, to prevent kidney damage caused by, for example, immunosuppressants such as cyclosporin A in organ transplants, as well as kidney cancer.
  • the compound (I) and its metabolites can be used for the prophylaxis and / or treatment of diabetes mellitus and diabetic sequelae such as e.g. Neuropathy and nephropathy.
  • the compound (I) and its metabolites may further be used for the prophylaxis and / or treatment of microalbuminuria, for example due to diabetes mellitus or hypertension, as well as proteinuria.
  • the compound (I) and its metabolites are also useful for the prophylaxis and / or treatment of diseases associated with either an increase in plasma glucocorticoid concentration or a local concentration elevation of glucocorticoid tissue (e.g., heart).
  • diseases associated with either an increase in plasma glucocorticoid concentration or a local concentration elevation of glucocorticoid tissue e.g., heart.
  • Examples include adrenal function disorders which lead to the overproduction of glucocorticoids (Cushing's syndrome), adrenocortical tumors with resulting overproduction of glucocorticoids, and pituitary tumors that autonomously produce ACTH (adrenocorticotropic hormone) and thus lead to adrenal hyperplasia with resultant Cushing's disease.
  • ACTH adrenocorticotropic hormone
  • the compound (I) and its metabolites can be used for the prophylaxis and / or treatment of obesity, metabolic syndrome and obstructive sleep apnea.
  • the compound (I) and its metabolites may be further used for the prophylaxis and / or treatment of inflammatory diseases, e.g. are caused by viruses, spirochetes, fungi, bacteria or mycobacteria, as well as inflammatory diseases of unknown aetiology, such as polyarthritis, lupus erythematosus, peri- or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • inflammatory diseases e.g. are caused by viruses, spirochetes, fungi, bacteria or mycobacteria
  • inflammatory diseases of unknown aetiology such as polyarthritis, lupus erythematosus, peri- or polyarteritis, dermatomyos
  • the compound (I) and its metabolites can be used for the treatment of central nervous disorders such as depression, anxiety and chronic pain, especially migraine, as well as in neurodegenerative diseases such as Alzheimer's disease and Parkinson's syndrome.
  • the compound (I) and its metabolites are also suitable for the prophylaxis and / or treatment of vascular damage, eg after interventions such as percutaneous transluminal coronary angioplasty (PTCA), implantations of stents, coronary angioscopy, reocclusion or restenosis after bypass.
  • PTCA percutaneous transluminal coronary angioplasty
  • stents e.g., adenothelial grafthelial grafta, CAD, reocclusion or restenosis after bypass.
  • Surgery as well as in endothelial dysfunction, in Raynaud's disease, in thrombangiitis obliterans (Buerger's syndrome) and in tinnitus syndrome.
  • Another object of the present invention is the use of the compound (I) and its metabolites for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compound (I) and its metabolites for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compound (I) may be used alone or as needed in combination with other drugs.
  • a further subject matter is medicaments containing a compound (I) and / or one or more metabolites and one or more further active compounds, in particular for the treatment and / or prevention of the abovementioned disorders.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • Hypotensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers and rho-kinase inhibitors;
  • Diuretics especially loop diuretics and thiazides and thiazide-like diuretics
  • Antithrombotic agents by way of example and preferably from the group of thrombocyte aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, AC AT inhibitors, CETP inhibitors, MTP inhibitors , PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorber, bile acid
  • cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, AC AT inhibitors, CETP inhibitors, MTP inhibitors , PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorber, bile acid
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • Positive-inotropic compounds such as cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
  • ABP atrial natriuretic peptide
  • BNP B-type natriuretic peptide
  • CNP C-type natriuretic peptide
  • urodilatin urodilatin
  • Calcium sensitizers such as by way of example and preferably levosimendan
  • NO-independent, but heme-dependent guanylate cyclase stimulators in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
  • Guanylate cyclase NO- and heme-independent activators in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
  • HNE human neutrophil elastase
  • the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib; and or
  • the energy metabolism of the heart affecting compounds such as by way of example and preferably etomoxir, dichloroacetate, ranolazines or trimetazidines.
  • compound (I) and its metabolites are used in combination with a diuretic such as, by way of example, furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone , Acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as, by way of example, furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethi
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptors B loosely, Rho-kinase Inhibitors and diuretics understood.
  • the compound (I) and / or one or more of its metabolites are administered in combination with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • compound (I) and / or one or more of its metabolites are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • the compound (I) and / or one or more of its metabolites are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • compound (I) and / or one or more of its metabolites are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compound (I) and / or one or more of its metabolites is combined with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP- 1148 administered.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP- 1148 administered.
  • compound (I) and / or one or more of its metabolites are administered in combination with an alpha-1 receptor blocker such as, for example, and preferably prazosin.
  • an alpha-1 receptor blocker such as, for example, and preferably prazosin.
  • compound (I) and / or one or more of its metabolites are used in combination with a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metabisole pranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker such as, by way of example and by way of preference, prop
  • the compound (I) and / or one or more of its metabolites is combined with a rho-kinase inhibitor, such as, for example and preferably, Fasilil, Y-27632, SLx-2119, BF-66851, BF-66852 BF-66853, KI-23095 or BA-1049.
  • a rho-kinase inhibitor such as, for example and preferably, Fasilil, Y-27632, SLx-2119, BF-66851, BF-66852 BF-66853, KI-23095 or BA-1049.
  • Antithrombotic agents are understood as meaning the compound (I) and / or one or more of its metabolites preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compound (I) and / or one or more of its metabolites are administered in combination with a platelet aggregation inhibitor, such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compound (I) and / or one or more of its metabolites are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • compound (I) is administered in combination with a GPIIb / IIIa antagonist, such as by way of example and preferably tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as by way of example and preferably tirofiban or abciximab.
  • the compound (I) and / or one or more of its metabolites in combination with a factor Xa inhibitor such as by way of example 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.
  • a factor Xa inhibitor such as by way of example and preferably riv
  • compound (I) and / or one or more of its metabolites is administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • compound (I) and / or one or more of its metabolites are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reab tion inhibitors, lipase inhibitors and the lipoprotein (a) understood antagonists.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers
  • compound (I) and / or one or more of its metabolites are combined with a CETP inhibitor, such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78- 7499 or CETP vaccine (Avant).
  • a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78- 7499 or CETP vaccine (Avant).
  • compound (I) and / or one or more of its metabolites will be used in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compound (I) and / or one or more of its metabolites is combined with an HMG-CoA reductase inhibitor from the class of statins such as, by way of example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, Rosu - vastatin, cerivastatin or pitavastatin.
  • statins such as, by way of example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, Rosu - vastatin, cerivastatin or pitavastatin.
  • the compound (I) and / or one or more of its metabolites are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compound (I) and / or one or more of its metabolites are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compound (I) and / or one or more of its metabolites are administered in combination with an MTP inhibitor, such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compound (I) and / or one or more of its metabolites are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • compound (I) and / or one or more of its metabolites are administered in combination with a PPAR delta agonist such as, for example and preferably, GW-501516 or BAY 68-5042.
  • a PPAR delta agonist such as, for example and preferably, GW-501516 or BAY 68-5042.
  • compound (I) and / or one or more of its metabolites are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compound (I) and / or one or more of its metabolites are administered in combination with a lipase inhibitor, such as by way of example and preferably orlistat.
  • the compound (I) and / or one or more of its metabolites are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • compound (I) and / or one or more of its metabolites are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • the invention also relates to medicaments which contain a compound of the formula (I) and / or one or more of its metabolites, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to their use for the purposes mentioned above.
  • the compound (I) and its metabolites can act systemically and / or locally.
  • they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compound (I) and its metabolites can be administered in suitable administration forms.
  • the prior art uses working forms which release the compound (I) and its metabolites rapidly and / or modified and which contain the compound according to the invention in crystalline and / or amorphised and / or dissolved form, e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a ⁇ ⁇ (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a ⁇ ⁇ e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions
  • Ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compound (I) and its metabolites can be converted into the mentioned administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • These adjuvants include, among others. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers ( For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • the present invention relates to the compounds of the formulas
  • a further subject of the present invention is a process for the preparation of the compound of the formulas Mla (S) and Mlb (R)
  • a further subject of the present invention is a process for the preparation of the compound of the formulas M2a (S) and M2b (R)
  • a further subject of the present invention is a process for the preparation of the compound of the formulas M3a (S) and M3b (R)
  • E. coli JM109 P450 3A4 was purchased from Oxford Biomedical Research.
  • Two 500 ml Erlenmeyer flasks were autoclaved with a nutrient solution (100 ml each) for 20 minutes at 121 ° C.
  • the nutrient solution consisted of tryptone (16 g 1-1), sodium chloride (10 g 1-1) and yeast extract (10 g 1-1) and was adjusted to pH 7.2-7.4 with 16% sodium hydroxide solution. After the sterilization process, ampicillin (100 mg 1-1) was added to the cooled flasks.
  • Both 500 ml Erlenmeyer flasks were each inoculated with a glycerol cryoculture (50 ⁇ ) of strain E. coli JM 109 P450 3A4. The flasks were shaken for 17 hours at 37 ° C and 165 rpm.
  • a 20-L fermentor was charged with tryptone (12 g 1-1), yeast extract (24 g 1-1), peptone from meat (2 g 1-1) [tryptically digested], potassium dihydrogen phosphate (2.2 g 1-1), dipotassium hydrogen phosphate (9.4 g 1-1) and 87% glycerol (4.6 g 1-1).
  • the medium was sterilized in the fermenter for 40 minutes at 121 ° C.
  • the following solutions were added: ampicillin (2.0 g) in water (20 ml), riboflavin (20 mg) in water (20 ml), thiamine hydrochloride (6.74 g) in water (10 ml) and Oxford trace element solution (5 ml ).
  • the pH and the phosphoric acid solution decreased was replaced with an aqueous glucose solution (50% glucose, sterile filtered). Now the aqueous glucose solution was added to keep the pH at 6.6.
  • cryopuffer cryopuffer: dipotassium hydrogen phosphate (12.3 g L 1 ), potassium dihydrogen phosphate (4 g L 1 ), glucose (100 ml - 50% aqueous solution), EDTA 0.5M, glycerol (40 ml H, 87%, 1313 ml) and stored
  • a 100-1 fermenter was charged with water (94 L), dipotassium hydrogen phosphate (1.23 Kg), potassium dihydrogen phosphate (400 g) and Synperonic (2.5 mL). The amount of buffer salts was calculated here to be 0.1 M at 100 l volume. Subsequently, the fermenter was sterilized for 40 minutes at 121 ° C. The volume after sterilization was 97 1. An aqueous glucose solution (2 L, 50% glucose, sterile filtered) and an EDTA solution (100 mL of a 0.5 M solution, final concentration 0.5 mM at 100 L volume) were added.
  • the educt (5 g, 13.28 mmol) was dissolved in DMF (200 ml) and added to the fermenter.
  • the fermenter was stirred at 70 rpm and 33.3 1 min-1 air.
  • 16% aqueous sodium hydroxide solution the pH was kept at 7.4.
  • Three cryopreserved cells (1200 ml each in 50% glycerol) were added at intervals of 15 minutes each time.
  • the oxygen partial pressure was kept at 50% by the stirrer speed. After 3 hours, the culture broth was harvested.
  • the culture broth was stirred for 18 hours with methyl isobutyl ketone (50 L) (32 rpm). The phases were separated and the aqueous phase was again stirred (32 rpm) with methyl isobutyl ketone (15 l) for 19 hours. The organic phases were concentrated separately. The concentrates were combined and concentrated to dryness. The solid residue was heated to reflux in methanol (200 mL). It was cooled and stored in the refrigerator overnight. The residue was filtered off with suction, washed with a little methanol and dried under vacuum at room temperature.
  • the crystal structure determination was carried out with the aid of a diffractometer (Oxford Diffraction,
  • Theta range for data acquisition 4.67 to 65.66 °.
  • the compound of formula Mlb (R) thus has the absolute configuration R
  • the absolute configuration is named according to the rules of Can-Ingold-Prelog for axially chiral connections
  • Figures 3-5 show the CD spectra of the compounds of the formulas Mlb (R), M2b (R) and M3b (R).
  • MR mineralocorticoid receptor
  • CHO Kl cell line an established chimera system is used in which the ligand-binding domains of human steroid hormone receptors are fused to the DNA binding domain of the yeast transcription factor GAL4.
  • the resulting GAL4 steroid hormone receptor chimeras are co-transfected in the CHO cells with a reporter construct and stably expressed.
  • the GAL4 DNA binding domain (amino acids 1-147) from the vector pFC2-dbd (from Stratagene) is ligated with the PCR-amplified ligand-binding domains of the mineralocorticoid receptor (MR, amino acids 734- 985), the glucocorticoid receptor (GR, amino acids 443-777), the progesterone receptor (PR, amino acids 680-933) and the androgen receptor (AR, amino acids 667-919) into the vector pIRES2 (Fa. Clontech) Moniert.
  • MR mineralocorticoid receptor
  • GR glucocorticoid receptor
  • PR progesterone receptor
  • AR amino acids 667-919
  • the reporter construct containing five copies of the GAL4 binding site upstream of a thymidine kinase promoter results in the expression of the firefly luciferase (Photinus pyralis) after activation and binding of the GAL4 steroid hormone receptor chimeras by the respective specific agonist aldosterone (MR), Dexamethasone (GR), progesterone (PR) and dihydrotestosterone (AR).
  • MR aldosterone
  • GR Dexamethasone
  • PR progesterone
  • AR dihydrotestosterone
  • the MR cells are plated in 96- (or 384- or 1536-) well microtiter plates (Optimem, 2.5% FCS, 2 mM glutamine, 10 mM HEPES) the day before the test and incubated in a cell incubator (96%). Humidity, 5%> v / v CO 2 , 37 ° C).
  • the substances to be tested are taken up in the above-mentioned medium and added to the cells. About 10 to 30 minutes after addition of the test substances, the respective specific agonists of the steroid hormone receptors are added.
  • the luciferase activity is measured by means of a video camera. The measured relative light units result in a sigmoidal stimulation curve as a function of the substance concentration.
  • the calculation of the IC50 values (in mol) is carried out with the help of the computogram GraphPad PRISM (Version 3.02).
  • Figure 1 Crystal structure of the compound of formula Mlb (R): (R) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide
  • Figure 2 Crystal structure of the compound of the formula Mlb (R): (R) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide

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Abstract

La présente invention concerne un nouveau procédé de préparation de (4R)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide de formule 4R (I) des métabolites de (4S)- et (4R)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide de formule (I), de formules M1a (S), Mlb (R), M2a (S), M2b (R), M3a (S) et M3b (R) et leur utilisation.
EP16750868.8A 2015-08-21 2016-08-15 Procédé de préparation de métabolites de (4s) et (4r)- 4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide et leur utilisation Withdrawn EP3337799A1 (fr)

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PCT/EP2016/069329 WO2017032627A1 (fr) 2015-08-21 2016-08-15 Procédé de préparation de métabolites de (4s) et (4r)- 4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide et leur utilisation

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WO2021254896A1 (fr) 2020-06-16 2021-12-23 Bayer Aktiengesellschaft Procédé de préparation de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide activé par une réduction catalytique asymétrique par esters de hantzsch

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