WO2009007028A1 - Dérivés promédicaments de 1-(4-méthoxyphényl)-7-oxo-6-[4-(2-oxopipéridin-1-yl)phényl]-4,5,6,7-tétrahydro-1h-pyrazolo[3,4-c]pyridine-3-carboxamide - Google Patents

Dérivés promédicaments de 1-(4-méthoxyphényl)-7-oxo-6-[4-(2-oxopipéridin-1-yl)phényl]-4,5,6,7-tétrahydro-1h-pyrazolo[3,4-c]pyridine-3-carboxamide Download PDF

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WO2009007028A1
WO2009007028A1 PCT/EP2008/005304 EP2008005304W WO2009007028A1 WO 2009007028 A1 WO2009007028 A1 WO 2009007028A1 EP 2008005304 W EP2008005304 W EP 2008005304W WO 2009007028 A1 WO2009007028 A1 WO 2009007028A1
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formula
compound
group
hydrogen
salts
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PCT/EP2008/005304
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German (de)
English (en)
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Hans-Georg Lerchen
Ursula Krenz
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Bayer Schering Pharma Aktiengesellschaft
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present application relates to prodrug derivatives of 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carboxamide, process for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular thromboembolic diseases.
  • Prodrugs are derivatives of an active substance which undergo a single or multistage biotransformation of enzymatic and / or chemical nature in vivo before the actual active substance is released.
  • a prodrug residue is usually used to improve the property profile of the underlying drug [P. Ettmayer et al., J. Med. Chem. 47, 2393 (2004)].
  • the design of the prodrug residue as well as the desired release mechanism must be tailored very precisely to the individual drug, the indication, the site of action and the route of administration.
  • a large number of drugs are administered as prodrugs which have improved bioavailability over the underlying drug, for example, by improving the physicochemical profile, especially solubility, active or passive absorption properties, or tissue specific distribution. Examples of the extensive literature on prodrugs are: H. Bundgaard (Ed.), Design of Prodrugs: Bioreversible Derivatives for Various Functional Groups and Chemical Entities, Elsevier Science Publishers B.V., 1985.
  • compound (A) has only a limited solubility in water and physiological media, which makes it difficult, for example, an intravenous administration of the drug.
  • the object of the present invention was therefore the identification of derivatives or prodrugs of compound (A), which have an improved solubility in said media and at the same time after application allow a controlled release of the active ingredient (A) in the body of the patient.
  • WO 2005/028473 describes, as prodrugs for carboxylic acid amides, acyloxymethylcarbamate prodrugs of oxazolidinones which serve to increase oral bioavailability.
  • WO 01/00622 discloses acyl prodrugs of carbamate inhibitors of inosine-5'-monophosphate dehydrogenase.
  • Another type of amide prodrugs, which release the underlying active ingredient via a multi-stage activation mechanism, is described for oxazolidinones in WO 03/006440.
  • the present invention relates to compounds of the general formula
  • R 1 is hydrogen or C 1 -C 4 -alkyl, wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy and C 1 -C 4 -alkoxy,
  • R 2 is hydrogen or C r C 4 alkyl
  • L is a C 1 -C 4 -alkanediyl group in which a CH 2 group can be exchanged for an O atom
  • R 3 is the side group of a natural ⁇ -amino acid or its homologs or isomers
  • R 1 and R 3 are linked via a (CH 2 ) 3 or (CH 2 ) 4 group and together with the nitrogen or carbon atom to which they are attached form a 5- or 6-membered ring,
  • R 4 is hydrogen or methyl
  • R 5 is C r C 4 alkyl
  • R 6 is hydrogen or C 1 -C 4 -alkyl
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the following compounds are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Suitable salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • Alkyl per se and "Alk” and "alkyl” in alkoxy represents a linear or branched alkyl radical having usually 1 to 4, preferably 1 or 2 carbon atoms, by way of example and preferably Methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkoxy is exemplified and preferably methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.
  • the side group of an ⁇ -amino acid in the meaning of R 3 includes both the side groups of the naturally occurring ⁇ -amino acids and the side groups of homologues and isomers of these ⁇ -amino acids.
  • the ⁇ -amino acid can be present in both the L and the D configuration or else as a mixture of the L and D form.
  • side groups are exemplified: hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropane -l-yl (isoleucine), butan-1-yl (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (Histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (5-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl ( Methionine), carbamoylmethyl (asparagine), 2-
  • Preferred ⁇ -amino acid side groups in the meaning of R 2 are hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), imidazol-4-ynethyl (histidine), Hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 3 Guanidino-propan-1-yl (arginine).
  • the L configuration is preferred.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one or two identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • R 1 is hydrogen or C 1 -C 4 -alkyl
  • R 2 is hydrogen
  • L is a C 2 -C 4 alkanediyl group
  • R 3 is hydrogen, methyl, propan-2-yl, propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoybnethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropane is -l-yl or 3-guanidinopropan-1-yl,
  • R 1 and R 3 are linked via a (CE 1 - or (CH 2 ) 4 group and together with the nitrogen or carbon atom to which they are attached form a 5- or 6-membered ring,
  • R 4 is hydrogen or methyl
  • R 5 is methyl
  • R 6 is hydrogen or methyl
  • R 1 is hydrogen, methyl or n-butyl
  • R 2 is hydrogen
  • L is a CH 2 CH 2 group or a group of the formula
  • R 3 is hydrogen, methyl, propan-2-yl, propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropane is -l-yl or 3-guanidinopropan-1-yl,
  • R 1 and R 3 are linked via one (CH 2 V ° of the (CH 2 ) 4 group and together with the nitrogen or carbon atom to which they are attached form a 5- or 6-membered ring,
  • R 4 is hydrogen or methyl
  • R 6 is hydrogen or methyl
  • Another object of the invention is a process for the preparation of the compounds of formula (I), characterized in that either
  • Q is a leaving group such as chlorine, bromine or iodine
  • PG is an amino-protecting group such as tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z)
  • R 4 alkyl of Ci-C where alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of hydroxy and C r C 4 alkoxy,
  • L 1 is a C 1 -C 4 -alkanediyl group in which a CH 2 group can be exchanged for an O atom
  • PG 1 and PG 2 independently of one another represent an amino-protecting group such as, for example, tert.-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or p-methoxybenzyl (PMB) and may be identical or different,
  • the compounds of the formulas (I-A), (I-B) and (I-C) can also be produced directly in the form of their salts in the preparation according to the processes described above. If desired, these salts can be converted into the respective free bases by treatment with a base in an inert solvent, by chromatographic methods or by means of ion exchange resins.
  • Such protective groups optionally present in R 1 , R 1A and / or R 3 can be removed simultaneously with the removal of PG or in a separate reaction step before or after the removal of PG.
  • amino-protecting group PG PG 1 or PG 2 , tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or p-methoxybenzyl (PMB) is preferably used in the above processes.
  • the cleavage of these protecting groups is carried out by conventional methods, preferably by reaction with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid in an inert solvent such as dioxane, dichloromethane or acetic acid; if appropriate, the cleavage can also be carried out without an additional inert solvent.
  • the process step (IH) + (IV) -> (V) is preferably carried out in N, N-dimethylformamide as solvent.
  • the reaction is carried out in a temperature range of 0 0 C to +50 0 C, forthcoming added at +20 0 C to + 50 ° C, carried out at atmospheric pressure.
  • the reaction can also be carried out advantageously under ultrasound treatment.
  • the compounds of the formulas (ET), (IV), (VI) and (VIH) are commercially available, known from the literature or can be prepared by methods customary in the literature.
  • the preparation of the compounds (A) is described in WO 03/026652 and WO 03/049681.
  • the compounds according to the invention and their salts are useful prodrugs of the active ingredient compound (A).
  • they On the one hand, they have good stability, for example at pH 4, and on the other hand show efficient conversion to the active compound (A) in vivo.
  • the compounds of the invention have a good solubility in water and other physiologically acceptable media, which makes them suitable for therapeutic use, especially in intravenous administration.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably of thromboembolic diseases and / or thromboembolic complications.
  • thromboembolic disorders include in particular diseases such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and Restenosis following coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusive disease, pulmonary embolism, deep venous thrombosis and renal vein thrombosis, transient ischemic attacks and thrombotic and thromboembolic stroke.
  • diseases such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI)
  • stable angina pectoris such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI)
  • unstable angina pectoris unstable angina pectoris
  • reocclusions and Restenosis following coronary interventions such as angioplasty or aortocoronary bypass
  • the substances are therefore also useful in the prevention and treatment of cardiogenic thromboembolism, such as brain ischemia, stroke and systemic thromboembolism and ischaemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion patients with valvular heart disease or with artificial heart valves.
  • cardiogenic thromboembolism such as brain ischemia, stroke and systemic thromboembolism and ischaemia
  • cardiac arrhythmias such as atrial fibrillation
  • the compounds of the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the musculoskeletal system, moreover also for the prophylaxis and / or treatment of Alzheimer's disease.
  • the compounds of the present invention can inhibit tumor growth and metastasis, microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases, and for the prevention and treatment of thromboembolic complications such as venous thromboembolism. in tumor patients, especially those undergoing major surgery or chemo- or radiotherapy.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the inventive compounds for the preparation of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using the compounds of the invention.
  • compositions containing a compound of the invention and one or more other active ingredients are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • Lipid-lowering agents in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors
  • Coronary / vasodilators especially ACE (angiotensin converting enzyme) inhibitors; AII (angiotensin II) receptor antagonists; beta-adrenoceptor antagonists; alpha 1-adrenoceptor antagonists; diuretics; Calcium channel blockers; Substances that one
  • cGMP cyclic guanosine monophosphate
  • plasminogen activators thrombolytics / fibrinolytics
  • thrombolysis / fibrinolysis-enhancing compounds such as inhibitors of plasminogen activator inhibitor (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitor (TAFI inhibitors);
  • anticoagulant substances anticoagulants
  • platelet aggregation inhibiting substances platelet aggregation inhibitors, antiplatelet agents
  • Fibrinogen receptor antagonists (glycoprotein IIb / ⁇ ia antagonists); • as well as antiarrhythmic drugs.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary or nasal. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • 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
  • tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalative dosage forms such as powder inhalers or nebulizers
  • nasally administrable dosage forms such as drops, solutions or sprays.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers eg, albumin
  • stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odor remedies include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (eg, albumin
  • 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.
  • Method 1 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min - »2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 2 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • Method 3 Device Type MS: Micromass ZQ; Device Type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5ml 50 % formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min, oven: 50 ° C, UV detection: 210 nm.
  • Method 5 Device Type HPLC: Abimed / Gilson Pump 305/306; Manometric Module 806; UV Knauer Variable Wavelength Monitor; Column: Gromsil C 18, 10 nm, 250 mm x 30 mm; Eluent A: 1 1 water + 0.5 ml 99% trifluoroacetic acid, eluent B: 1 liter acetonitrile; Gradient: 0.0 min 2% B ⁇ 10 min 2% B ⁇ 50 min 90% B; Flow: 20 ml / min; Volume: 628 ml A and 372 ml B.
  • Method 6a (preparative HPLC): Column: VP 250/21 Nucleodur 100-5 C18 ec, Macherey & Nagel No. 762002; Eluent A: water / 0.01% trifluoroacetic acid, eluent B: acetonitrile / 0.01% trifluoroacetic acid; Gradient: 0 min 0% B ⁇ 20 min 20% B ⁇ 40 min 20% B ⁇ 60 min 30% B ⁇ 80 min 30% B ⁇ 90 min 100% B ⁇ 132 min 100% B; Flow: 5 ml / min; Temperature: RT; UV detection: 210 nm.
  • Method 6b (preparative HPLC): column: VP 250/21 Nucleodur 100-5 Cl 8 ec, Macherey & Nagel No. 762002; Eluent A: 1 1 water / 1 ml 99% trifluoroacetic acid, eluent B: 1 liter acetonitrile / 1 ml 99% trifluoroacetic acid; Gradient: 0 min 30% B ⁇ 20 min 50% B ⁇ 40 min 80% B ⁇ 60 min 100% B; Flow: 5 ml / min; Temperature: RT; UV detection: 210 nm.
  • Method 7 Analytical HPLC: Column: XTerra 3.9 x 150 WAT 186000478; Eluent A: 10 ml of 70% perchloric acid in 2.5 liters of water, eluent B: acetonitrile; Gradient: 0.0 min 20% B -> 1 min 20% B ⁇ 4 min 90% B ⁇ 9 min 90% B; Temperature: RT; Flow: 1 ml / min.
  • Method 8 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ⁇ 2 min 65% A ⁇ 4.5 min 5% A ⁇ 6 min 5% A; Flow: 2 ml / min; Oven: 40 ° C; UV detection: 208-400 nm.
  • Method 9 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ , 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A ⁇ 0.2 min 100% A ⁇ 2.9 min 30% A ⁇ 3.1 min 10% A ⁇ 5.5 min 10% A; Oven: 50 ° C .; Flow: 0.8 ml / min; UV detection: 210 nm.
  • Method 10 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2.5 ⁇ MAX-RP 100A Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - * 0.1 min 90% A -> 3.0 min 5% A - »4.0 min 5% A - * 4.01 min 90% A; Flow: 2 ml / min ;; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 11 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2.5 ⁇ MAX-RP 100A Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A -> 3.0 min 5% A -> 4.0 min 5% A -> 4.1 min 90% A; Flow: 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • Method 12 Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50mm x 1mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - ⁇ 0.1 min 90% A -> 1.5 min 10% A - »2.2 min 10% A; Oven: 50 ° C .; Flow: 0.33 ml / min; UV detection: 210 nm.
  • the starting material was 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4- c] pyridine-3-carboxamide [compound (A)] whose preparation is described elsewhere [WO 03026652, WO 03049681].
  • 3 - [[(benzyloxy) carbonyl] (methyl) amino] propionic acid via the introduction of the benzyloxycarbonyl protective group into the corresponding ⁇ -N-methylamino-alkylcarboxylic acid, which according to P. Quitt et al. [Helv. Chim. Acta 46, 327 (1963)].
  • 3 - [[(benzyloxy) carbonyl] (methyl) amino] propionic acid may be prepared according to the literature [Y. Aramaki et al., Chem. Pharm. Bull. 52, 258 (2004)] can be prepared from commercially available 3 - ⁇ [(benzyloxy) carbonyl] amino ⁇ propionic acid.
  • 6 - [[(benzyloxy) carbonyl] (methyl) amino] caproic acid was prepared via the introduction of the benzyloxycarbonyl protective group into the corresponding co-N-methylamino-alkylcarboxylic acid, which according to P. Quitt et al. [Helv. Chim. Acta 46, 327 (1963)].
  • 6 - [[(benzyloxy) carbonyl] (methyl) amino] caproic acid may be prepared according to literature [Y. Aramaki et al., Chem. Pharm. Bull. 52, 258 (2004)] from commercially available 6 - ⁇ [(benzyloxy) carbonyl] amino ⁇ caproic acid.
  • Example IA 62 mg (116 ⁇ mol) of Example IA were dissolved with 50 mg (162 ⁇ mol) of the cesium salt of Boc-glycine (prepared from Boc-glycine according to General Procedure 1) in 10 ml of DMF. One stirred at RT overnight and then narrowed. The remaining residue was purified by preparative HPLC (Method 6a). The appropriate fractions were combined, concentrated and the residue dried under high vacuum. The protected intermediate was isolated together with a by-product and initially used without further purification in the next step.
  • test substance is suspended in water pH 4 or in 5% dextrose solution pH 4. This suspension is shaken for 24 h at room temperature. After ultra-centrifugation at 224000g for 30 min, the supernatant is diluted with DMSO and analyzed by HPLC. Quantification is via a two-point calibration curve of the test compound in DMSO.
  • Agilent 1100 with DAD (Gl 315A), quat. Pump (G131 IA), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: Phenomenex Gemini C18, 5 ⁇ m, 50 mm x 2 mm; Temperature: 40 ° C .; Eluent A: water / phosphoric acid pH 2, eluent B: acetonitrile; Flow rate: 0.7 ml / min; Gradient: 0-0.5 min 85% A, 15% B; Ramp 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; Ramp 3.5-4 min 85% A, 15% B; 4-5 minutes 85% A, 15% B.
  • Agilent 1100 with DAD (G1315A), quat. Pump (G131 IA), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: VDSoptilab Kromasil 100 Cl 8, 3.5 ⁇ m, 60 mm x 2.1 mm; Temperature: 30 ° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Flow rate: 0.75 ml / min; Gradient: 0-0.5 min 98% A, 2% B; Ramp 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; Ramp 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.
  • test substance from Example 1 was in water pH 4 or in 5% dextrose solution at pH 4 and the test substance from Example 2 was suspended in 5% dextrose solution. Under the conditions indicated, the compounds of Examples 1 and 2 had a solubility of more than 500 mg / l each.
  • test substance 0.3 mg are weighed into a 2 ml HPLC vial and mixed with 0.5 ml of acetonitrile. To dissolve the substance, the sample vessel is placed in the ultrasonic bath for approx. 10 seconds. Subsequently, 0.5 ml of the respective buffer solution is added and the sample is again treated in an ultrasonic bath.
  • pH 4.0 1 liter of Millipore water is adjusted to pH 4.0 with 1 N hydrochloric acid; pH 7.4: 90 g of sodium chloride, 13.61 g of potassium dihydrogen phosphate and 83.35 g of 1 N sodium hydroxide solution are made up to 1 liter with Millipore water.
  • Agilent 1100 with DAD (G1314A), binary pump (GI 312A), autosampler (G 1329A), column oven (G1316A), thermostat (GI 330A); Column: Kromasil 100 C18, 125 mm x 4 mm, 5 ⁇ m; Column temperature: 30 ° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Gradient: 0- 3.0 min 80% A, 20% B; 3.0-18.0 min 80% A, 20% B; 18.0-20.0 min 10% A, 90% B; 20.0-21.0 min 10% A, 90% B; 21.0-23.0 90% A, 10% B; 23.0-26.0 90% A, 10% B; Flow rate: 2.0 ml / min; UV detection: 278 nm.
  • Table 2 shows, for representative embodiments, the ratios of the peak areas (F) at the respective times in relation to the peak areas at the start time:
  • Agilent 1100 with DAD (G 1314A), binary pump (G 1312A), autosampler (G 1329A), column oven (G1316A), thermostat (G1330A); Column: Kromasil 100 Cl 8, 250 mm ⁇ 4 mm, 5 ⁇ m; Column temperature: 30 ° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile; Gradient: 0-7.0 min 71% A, 29% B; 7.0-18.0 min 71% A, 29% B; 18.0-20.0 min 10% A, 90% B; 20.0-21.0 min 10% A, 90% B; 21.0-22.5 min 98% A, 2% B; 22.5-25.0 min 98% A, 2% B; Flow rate: 2 ml / min; UV detection: 278 nm.
  • Table 3 shows the respective times for representative embodiments in which 50% of the maximum possible amount of active substance compound (A) has arisen (t 50% A ). For the evaluation, the ratio of the peak areas to the individual times with respect to the starting point was used in each case.
  • test substance On the day of the test, a defined dose of the test substance is administered as a solution with a Hamilton ® glass syringe into the tail vein (bolus administration, application time ⁇ 10 s). Within 24 hours of substance administration, blood samples (8-12 times) are taken sequentially across the catheter. For plasma collection, the samples are centrifuged in heparinized tubes. At each point in time, a defined plasma volume for protein precipitation is mixed with acetonitrile. After centrifugation, test substance and optionally known cleavage products of the test substance quantified in the supernatant with a suitable LC / MS-MS method.
  • Fasting male rats (strain: HSD CPB: WU) are anesthetized by intraperitoneal administration of a Rompun / Ketavet solution (12 mg / kg / 50 mg / kg). Thrombus formation is performed in an arteriovenous shunt following the procedure described by PC Wong et al. described method [Thrombosis Research 83 (2), 117-126 (1996)]. For this purpose, the left jugular vein and the right carotid artery are dissected free.
  • An 8 cm long polyethylene catheter (PE60, Becton-Dickinson) is inserted into the artery, followed by a 6 cm long Tygon tube (R-3606, ID 3.2 mm, from Kronlab), which is roughened to produce a thrombogenic surface and to a double loop nylon thread (60 x 0.26 mm, Berkley Trilene) included.
  • a 2 cm long polyethylene catheter (PE60, Becton-Dickinson) is integrated and connected to the Tygon tube via a 6 cm long polyethylene catheter (PE 160, Becton-Dickinson).
  • the tubes are filled with saline before opening the shunt. The extracorporeal circuit is maintained for 15 minutes.
  • test substance as a solution in physiological saline adjusted to pH 4 with 0.1N hydrochloric acid
  • the test substance is administered as a bolus injection prior to application of the extracorporeal circuit.
  • the compounds according to the invention can be converted, for example, into pharmaceutical preparations as follows:
  • the compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (for example isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%, which are each adjusted to a pH of 3-5) ,
  • a physiologically tolerated solvent for example isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%, which are each adjusted to a pH of 3-5
  • the solution is optionally filtered sterile and / or filled into sterile and pyrogen-free injection containers.

Abstract

La présente invention concerne des dérivés promédicaments de 1-(4-méthoxyphényl)-7-oxo-6-[4-(2-oxopipéridin-1-yl)phényl]-4,5,7-tétrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, leur procédé de fabrication, leur utilisation pour le traitement et/ou la prophylaxie de maladies et leur utilisation pour la fabrication de médicaments pour le traitement et/ou la prophylaxie de maladies, notamment de maladies thromboemboliques.
PCT/EP2008/005304 2007-07-11 2008-06-28 Dérivés promédicaments de 1-(4-méthoxyphényl)-7-oxo-6-[4-(2-oxopipéridin-1-yl)phényl]-4,5,6,7-tétrahydro-1h-pyrazolo[3,4-c]pyridine-3-carboxamide WO2009007028A1 (fr)

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DE102007032344A DE102007032344A1 (de) 2007-07-11 2007-07-11 Prodrug-Derivate von 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-carboxamid

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WO2014202027A1 (fr) * 2013-06-21 2014-12-24 四川海思科制药有限公司 Dérivé spirocyclique de 4,5-dihydropyrazolo[3,4-c]pyridine-2-one et procédé de préparation et d'utilisation associé
WO2015051713A1 (fr) * 2013-10-11 2015-04-16 四川海思科制药有限公司 Dérivé de spiro-4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one, son procédé de préparation et son utilisation
WO2015081901A1 (fr) * 2013-12-06 2015-06-11 四川海思科制药有限公司 Dérivé spirocyclique de 4,5-dihydropyrazolo[3,4-c] pyridine-2-one substitué, et utilisation dudit dérivé

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WO2003049681A2 (fr) * 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthese de 4,5-dihydropyrazolo[3,4-c]pyrid-2-ones

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WO2014202027A1 (fr) * 2013-06-21 2014-12-24 四川海思科制药有限公司 Dérivé spirocyclique de 4,5-dihydropyrazolo[3,4-c]pyridine-2-one et procédé de préparation et d'utilisation associé
CN104395312A (zh) * 2013-06-21 2015-03-04 四川海思科制药有限公司 4,5-二氢吡唑并[3,4-c]吡啶-2-酮的螺环衍生物、其制备方法以及应用
WO2015051713A1 (fr) * 2013-10-11 2015-04-16 四川海思科制药有限公司 Dérivé de spiro-4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one, son procédé de préparation et son utilisation
CN105324382A (zh) * 2013-10-11 2016-02-10 四川海思科制药有限公司 4,5-二氢吡唑并[3,4-c]吡啶-2-酮的螺环衍生物、其制备方法以及应用
CN105324382B (zh) * 2013-10-11 2017-11-10 四川海思科制药有限公司 4,5‑二氢吡唑并[3,4‑c]吡啶‑2‑酮的螺环衍生物、其制备方法以及应用
WO2015081901A1 (fr) * 2013-12-06 2015-06-11 四川海思科制药有限公司 Dérivé spirocyclique de 4,5-dihydropyrazolo[3,4-c] pyridine-2-one substitué, et utilisation dudit dérivé
CN105745212A (zh) * 2013-12-06 2016-07-06 四川海思科制药有限公司 取代的4,5-二氢吡唑并[3,4-c]吡啶-2-酮的螺环衍生物及应用

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