Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • 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
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the invention relates to novel substituted piperidines, to processes for preparation thereof, to the use thereof for treatment and/or prophylaxis of diseases and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of cardiovascular disorders and tumour disorders.
• Thrombocytes blood platelets
• platelets are of central importance in the complex interaction between blood components and the wall of the vessel. Unwanted platelet activation may, through formation of platelet-rich thrombi, result in thromboembolic disorders and thrombotic complications with life-threatening conditions.
• thrombin is formed at injured blood vessel walls and which, in addition to fibrin formation, leads to the activation of platelets, endothelial cells and mesenchymal cells (Vu T K H, Hung D T, Wheaton V I, Coughlin S R, Cell 1991, 64, 1057-1068).
• thrombin inhibitors inhibit platelet aggregation and the formation of platelet-rich thrombi.
• arterial thromboses can be prevented or treated successfully with inhibitors of platelet function and thrombin inhibitors (Bhatt D L, Topol E J, Nat. Rev. Drug Discov. 2003, 2, 15-28).
• thrombin action on platelets will reduce the formation of thrombi and the occurrence of clinical sequelae such as myocardial infeaction and stroke.
• Other cellular effects of thrombin for example on endothelial cells and smooth-muscle cells of vessels, on leukocytes and on fibroblasts, are possibly responsible for inflammatory and proliferative disorders.
• thrombin a family of G-protein-coupled receptors (Protease Activated Receptors, PARs), the prototype of which is the PAR-1 receptor.
• PAR-1 is activated by udi of thrombin and proteolytic cleavage of its extracellular N-terminus. The proteolysis exposes a new N-terminus having the amino acid sequence SFLLRN . . . , which, as an agonist (“tethered ligand”) leads to intramolecular receptor activation and transmission of intracellular signals.
• Peptides derived from the tethered-ligand sequence can be used as agonists of the receptor and, on platelets, lead to activation and aggregation.
• proteases are likewise capable of activating PAR-1, including, for example, plasmin, factor VIIa, factor Xa, trypsin, activated protein C (aPC), tryptase, cathepsin G, proteinase 3, granzyme A, elastase and matrix metalloprotease 1 (MMP-1).
• PAR-1 including, for example, plasmin, factor VIIa, factor Xa, trypsin, activated protein C (aPC), tryptase, cathepsin G, proteinase 3, granzyme A, elastase and matrix metalloprotease 1 (MMP-1).
• blockade of PAR-1 should result in an inhibition of platelet activation without reduction of the coagulability of the blood (anticoagulation).
• Antibodies and other selective PAR-1 antagonists inhibit the thrombin-induced aggregation of platelets in vitro at low to medium thrombin concentrations (Kahn M L, Nakanishi-Matsui M, Shapiro M J, Ishihara H, Coughlin S R, J. Clin. Invest. 1999, 103, 879-887).
• PAR-1 antagonists reduce the formation of platelet-rich thrombi (Derian C K, Damiano B P, Addo M F, Darrow A L, D'Andrea M R, Nedelman M, Zhang H-C, Maryanoff B E, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861).
• thrombin which are mediated via the PAR-1 receptor affect the progression of disease during and after coronary artery bypass graft (CABG) and other operations and especially operations with extracorporeal circulation (for example heart-lung machine).
• CABG coronary artery bypass graft
• extracorporeal circulation for example heart-lung machine.
• CABG coronary artery bypass graft
• DIC disseminated intravascular coagulation or consumption coagulopathy
• the PAR-1 receptor is also expressed in other cells including, for example, endothelial cells, smooth muscle cells and tumour cells.
• Malignant tumour disorders have a high incidence and are generally associated with high mortality.
• Current therapies achieve full remission in only a fraction of patients and are typically associated with severe side effects. There is therefore a great need for more effective and safer therapies.
• the PAR-1 receptor contributes to cancer generation, growth, invasiveness and metastasis.
• angiogenesis vascular growth
• Angiogenesis also contributes to the genesis or worsening of other disorders including, for example, haematopoetic cancer disorders, macular degeneration, which leads to blindness, and diabetic retinopathy, inflammatory disorders, such as rheumatoid arthritis and colitis.
• Sepsis (or septicaemia) is a frequent disorder with high mortality.
• Initial symptoms of sepsis are typically unspecific (for example fever, reduced general state of health); however, there may later be generalized activation of the coagulation system (“disseminated intravascular coagulation” or “consumption coagulopathy” (DIC)) with the formation of microthrombi in various organs and secondary bleeding complications.
• DIC may also occur independently of a sepsis, for example in the course of operations or in the event of tumour disorders.
• Treatment of sepsis consists firstly in the rigorous elimination of the infectious cause, for example by operative removal of the focus and antibiosis. Secondly, it consists in temporary intensive medical support of the affected organ systems. Treatments of the different stages of this disease have been described, for example, in the following publication (Dellinger et al., Crit. Care Med. 2004, 32, 858-873). There are no proven effective treatments for DIC.
• WO 2006/012226, WO 2006/020598, WO 2007/038138, WO 2007/130898, WO 2007/101270 and US 2006/0004049 describe structurally similar piperidines as 11- ⁇ HSD1 inhibitors for treatment of diabetes, thromboembolic disorders and stroke, among other disorders.
• the invention provides compounds of the formula
• Inventive compounds are the compounds of the formula (I) and their salts, solvates and solvates of the salts; the compounds, encompassed by formula (I), of the formulae below and their salts, solvates and solvates of the salts, and the compounds encompassed by formula (I) specified below as working examples and their salts, solvates and solvates of the salts, if the compounds, encompassed by formula (I), below are not already salts, solvates and solvates of the salts.
• inventive compounds may exist in stereoisomeric forms (enantiomers, diastereomers).
• the invention therefore encompasses the enantiomers or diastereomers and their respective mixtures. It is possible to isolate the stereoisomerically uniform constituents in a known manner from such mixtures of enantiomers and/or diastereomers.
• inventive compounds can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
• preferred salts are physiologically acceptable salts of the inventive compounds.
• salts which themselves are not suitable for pharmaceutical applications, but which can be used, for example, for the isolation or purification of the inventive compounds.
• Physiologically acceptable salts of the inventive compounds include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene disulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene disulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, mal
• Physiologically acceptable salts of the inventive compounds also include salts of customary bases, such as, by way of example and with preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and with preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
• customary bases such as, by way of example and with preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salt
• solvates are those forms of the inventive compounds which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water.
• the present invention also encompasses prodrugs of the inventive compounds.
• prodrugs encompasses compounds which themselves may be biologically active or inactive but which, during their residence time in the body, are converted to inventive compounds (for example metabolically or hydrolytically).
• Alkyl per se and “alk” and “alkyl” in alkoxy, alkylamino, alkylcarbonyl, alkylaminocarbonyl and alkylsulphonyl are a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, by way of example and with preference methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.
• alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
• Alkylamino is an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and with preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and N-tert-butyl-N-methylamino C 1 -C 4 -Alkylamino is, for example, a monoalkylamino radical having 1 to 4 carbon atoms or is a dialkylamino radical having in each case 1 to 4 carbon atoms per alkyl substituent.
• alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.
• Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and with preference methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.
• C 1 -C 4 -Alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 4 carbon atoms or is a dialkylaminocarbonyl radical having in each case 1 to 4 carbon atoms per alkyl substituent.
• alkylsulphonyl is methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl and tert-butylsulphonyl.
• Cycloalkyl is a monocyclic cycloalkyl group having generally 3 to 7, preferably 5 or 6, carbon atoms; examples of preferred cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• Cycloalkyloxy is a monocyclic cycloalkyloxy group having generally 3 to 7, preferably 5 or 6, carbon atoms; examples of preferred cycloalkyloxys are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
• Cycloalkylamino is a monocyclic cycloalkylamino group having generally 3 to 7, preferably 3 or 4, carbon atoms; examples of preferred cycloalkylaminos are cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino.
• Heterocyclyl is a monocyclic or bicyclic, heterocyclic radical having 4 to 7 ring atoms and up to 3, preferably up to 2, heteroatoms and/or hetero groups from the group consisting of N, O, S, SO, SO 2 , where one nitrogen atom may also form an N-oxide.
• the heterocyclyl radicals may be saturated or partially unsaturated.
• 5- or 6-membered monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the group consisting of O, N and S by way of example and with preference oxetanyl, azetidinyl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxidothiomorpholin-4-
• Heterocyclylamino is a monocyclic or bicyclic, heterocyclic heterocyclylamino radical having 4 to 7 ring atoms and up to 3, preferably up to 2, heteroatoms and/or hetero groups from the group consisting of N, O, S, SO, SO 2 , where one nitrogen atom may also form an N-oxide.
• the heterocyclyl radicals may be saturated or partially unsaturated.
• 5- or 6-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatomen from the group consisting of O, N and S for example and with preference oxetanylamino, azetidinylamino, pyrrolidin-2-ylamino, pyrrolidin-3-ylamino, tetrahydrofuranylamino, tetrahydrothienylamino, pyranylamino, piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-yl-amino, 1,2,5,6-tetrahydropyridin-3-ylamino, 1,2,5,6-tetrahydropyridin-4-ylamino, thiopyranylamino, morpholin-2-ylamino, morpholin-3-ylamino, thiomorpholin-2-ylamino, thiomorpholin-3-ylamino, piperazin-2-yla
• Heteroaryl is an aromatic monocyclic radical having generally 5 or 6 ring atoms and up to 4 heteroatoms from the group consisting of S, O and N, where one nitrogen atom may also form an N-oxide, by way of example and with preference thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.
• Heteroarylamino is an aromatic monocyclic heteroarylamino radical having generally 5 or 6 ring atoms and up to 4 heteroatoms from the group consisting of S, O and N, where one nitrogen atom may also form an N-oxide, by way of example and with preference thienylamino, furylamino, pyrrolylamino, thiazolylamino, oxazolylamino, isoxazolylamino, oxadiazolylamino, pyrazolylamino, imidazolylamino, pyridylamino, pyrimidylamino, pyridazinylamino, pyrazinylamino.
• Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
• R 1 is phenyl
• phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, methylsulphonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkoxycarbonyl.
• R 1 is phenyl, where phenyl is substituted by 1 to 3 substituents selected independently from the group consisting of trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkoxycarbonyl.
• R 1 is phenyl, where phenyl is substituted by 1 to 2 substituents selected independently from the group consisting of trifluoromethyl, trifluoromethoxy, methyl, ethyl and methoxy.
• R 1 is phenyl, where phenyl is substituted by one substituent in the para position to the site of attachment to the piperidine ring, selected from the group consisting of trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy and ethyl.
• R 1 is phenyl, where phenyl is substituted by one substituent in the para position to the site of attachment to the piperidine ring, selected from the group consisting of trifluoromethyl, trifluoromethoxy and ethyl.
• R 2 is methyl, ethyl or isopropyl, where ethyl may be substituted by one substituent selected from the group consisting of hydroxyl, methoxy and ethoxy.
• R 3 is morpholin-4-yl, thiomorpholin-4-yl, 1-oxidothiomorpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-1-yl or 4-hydroxypiperidin-1-yl.
• R 1 and R 2 are each as defined above or
• R 3 is as defined above and X 1 is halogen, preferably bromine or chlorine, or hydroxyl or 4-nitrophenoxy, or [F] compounds of the formula (XV) are reacted in the first stage with 4-nitrophenyl chloroformate and in the second stage with compounds of the formula
• R 3 is as defined above.
• the compounds of the formulae (Ia), (Ib) and (Ic) are a subset of the compounds of the formula (I).
• reaction according to process [A] is generally effected in inert solvents, optionally in the presence of molecular sieve, optionally in the presence of a base, preferably in a temperature range from room temperature to 100° C. at standard pressure.
• Inert solvents are, for example, ethers such as diethyl ether, dioxane or tetrahydrofuran, preference being given to dioxane.
• Bases are, for example, phosphazene P 4 base, or alkoxides such as sodium methoxide or sodium ethoxide, or other bases such as sodium hydride, preference being given to phosphazene P 4 base.
• reaction according to process [A] is generally effected in inert solvents, optionally with an excess of the compound of the formula (III), to give the compound of the formula (II), optionally in a microwave, preferably in a temperature range from 50° C. to 200° C. at standard pressure to 5 bar.
• Inert solvents are, for example, alcohols such as ethanol or methanol, or other solvents such as dimethyl sulphoxide, dimethylformamide or N-methylpyrrolidone, preference being given to ethanol.
• the compounds of the formula (III) are known or can be synthesized by known processes from the appropriate starting compounds.
• reaction according to process [B] is generally effected in inert solvents, in the presence of a dehydrating reagent, optionally in the presence of a base, preferably in a temperature range from room temperature up to reflux of the solvents at standard pressure.
• Inert solvents are, for example, halohydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile. It is equally possible to use mixtures of the solvents. Preference is given to dimethylformamide or a mixture of dioxane and dimethylformamide.
• Suitable dehydrating reagents in this context are, for example, carbodiimides, for example N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide), or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydr
• Bases are, for example, alkali metal carbonates, for example sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to diisopropylethylamine.
• alkali metal carbonates for example sodium carbonate or potassium carbonate
• sodium hydrogencarbonate or potassium hydrogencarbonate or organic bases
• organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to diisopropylethylamine.
• the condensation is performed with HATU in the presence of diisopropylethylamine or alternatively only with carbonyldiimidazole.
• the compounds of the formula (V) are known or can be synthesized by known processes from the appropriate starting compounds.
• reaction according to process [C] is generally performed in inert solvents, preferably in a temperature range of room temperature up to reflux of the solvents at standard pressure.
• meta-Chloroperbenzoic acid is preferably used in an amount of 0.9 to 1.0 equivalent.
• Inert solvents are, for example, halohydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane. Preference is given to methylene chloride.
• reaction according to process [D] is generally performed in inert solvents, preferably in a temperature range of room temperature up to reflux of the solvents at standard pressure.
• meta-Chloroperbenzoic acid is preferably used in an amount of 2.3 to 2.6 equivalents, more preferably in an amount of 2.5 equivalents.
• Inert solvents are, for example, halohydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane. Preference is given to methylene chloride.
• reaction according to process [E] is generally effected in inert solvents, optionally in the presence of a base, preferably in a temperature range of ⁇ 30° C. to 50° C. at standard pressure.
• Inert solvents are, for example, tetrahydrofuran, methylene chloride, pyridine, dioxane or dimethylformamide, preference being given to methylene chloride.
• Bases are, for example, triethylamine, diisopropylethylamine or N-methylmorpholine, preference being given to triethylamine or diisopropylethylamine
• reaction according to process [E] is generally effected in inert solvents, in the presence of a dehydrating reagent, optionally in the presence of a base, preferably in a temperature range of ⁇ 30° C. to 50° C. at standard pressure.
• Inert solvents are, for example, halohydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is equally possible to use mixtures of the solvents. Particular preference is given to dichloromethane or dimethylformamide
• Suitable dehydrating reagents in this context are, for example, carbodiimides, for example N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide), or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydr
• Bases are, for example, alkali metal carbonates, for example sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine
• the condensation is performed with HATU or with EDC in the presence of HOBt.
• reaction according to process [E] is generally effected in inert solvents, optionally in the presence of a base, optionally in a microwave, preferably in a temperature range of 50° C. to 200° C. at standard pressure to 5 bar.
• Inert solvents are, for example, N-methylpyrrolidone, dioxane or dimethylformamide, preference being given to N-methylpyrrolidone.
• Bases are, for example, triethylamine, diisopropylethylamine or N-methylmorpholine, preference being given to triethylamine or diisopropylethylamine
• the compounds of the formula (IX) are known or can be synthesized by known processes from the appropriate starting compounds.
• the first stage reaction according to process [F] is generally effected in inert solvents, in the presence of a base, preferably in a temperature range of 0° C. to 50° C. at standard pressure.
• Inert solvents are, for example, halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane or 1,2-dichloroethane, preference being given to methylene chloride.
• Bases are, for example, organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to triethylamine.
• organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to triethylamine.
• reaction of the second stage according to process [F] is generally effected in inert solvents, in the presence of a base, optionally in a microwave, preferably in a temperature range of 50° C. to 200° C. at standard pressure to 5 bar.
• Inert solvents are, for example, dimethyl sulphoxide, dimethylformamide or N-methylpyrrolidone, preference being given to dimethylformamide
• Bases are, for example, alkali metal carbonates, for example sodium carbonate or potassium carbonate, preference being given to potassium carbonate.
• the compounds of the formula (XVI) are known or can be synthesized by known processes from the appropriate starting compounds.
• R 1 and R 3 are each as defined above, with hydrogen chloride solution and sodium nitrite.
• the reaction is effected preferably in a temperature range of 0° C. up to reflux of the solvents at standard pressure.
• the compounds of the formula (VI) are known or can be prepared by reacting compounds of the formula (IV) with hydroxyguanidine hemisulphate hemihydrate.
• reaction is effected as described for process [B], optionally in the presence of molecular sieve.
• the compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula
• R 1 and R 3 are each as defined above and R 5 is methyl or ethyl, with a base.
• the reaction is generally effected in inert solvents, in the presence of a base, preferably in a temperature range of room temperature up to reflux of the solvents at standard pressure.
• Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium or potassium carbonate, or alkoxides such as potassium or sodium tert-butoxide, preference being given to lithium hydroxide or potassium tert-butoxide.
• R 3 is as defined above and X 1 is halogen, preferably bromine or chlorine, or hydroxyl or 4-nitrophenoxy.
• reaction is generally effected in inert solvents, optionally in the presence of a base, preferably in a temperature range of ⁇ 30° C. to 50° C. at standard pressure.
• Inert solvents are, for example, tetrahydrofuran, methylene chloride, pyridine, dioxane or dimethylformamide, preference being to methylene chloride.
• Bases are, for example, triethylamine, diisopropylethylamine or N-methylmorpholine, preference being given to triethylamine or diisopropylethylamine
• the reaction is generally effected in inert solvents, in the presence of a dehydrating reagent, optionally in the presence of a base, preferably in a temperature range of ⁇ 30° C. to 50° C. at standard pressure.
• Inert solvents are, for example, halohydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is equally possible to use mixtures of the solvents. Particular preference is given to dichloromethane or dimethylformamide
• Suitable dehydrating reagents in this context are, for example, carbodiimides, for example N,N′-diethyl-,N,N′-dipropyl-,N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide), or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydr
• Bases are, for example, alkali metal carbonates, for example sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
• alkali metal carbonates for example sodium carbonate or potassium carbonate
• organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
• the condensation is performed with HATU or with EDC in the presence of HOBt.
• the reaction is generally effected in inert solvents, optionally in the presence of a base, optionally in a microwave, preferably in a temperature range of 50° C. to 200° C. at standard pressure to 5 bar.
• Inert solvents are, for example, N-methylpyrrolidone, dioxane or dimethylformamide, preference being given to N-methylpyrrolidone.
• Bases are, for example, triethylamine, diisopropylethylamine or N-methylmorpholine, preference being given to triethylamine or diisopropylethylamine
• the compounds of the formula (IX) are known or can be synthesized by known processes from the appropriate starting compounds.
• the compounds of the formula (VII) can be prepared by reacting compounds of the formula (VIII) in the first stage with 4-nitrophenyl chloroformate and in the second stage with compounds of the formula
• R 3 is as defined above.
• Inert solvents are, for example, halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane or 1,2-dichloroethane, preference being given to methylene chloride.
• Bases are, for example, organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to triethylamine.
• organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to triethylamine.
• the reaction of the second stage is generally effected in inert solvents, in the presence of a base, optionally in a microwave, preferably in a temperature range of 50° C. to 200° C. at standard pressure to 5 bar.
• Inert solvents are, for example, dimethyl sulphoxide, dimethylformamide or N-methylpyrrolidone, preference being given to dimethylformamide.
• Bases are, for example, alkali metal carbonates, for example sodium carbonate or potassium carbonate, preference being given to potassium carbonate.
• the compounds of the formula (X) are known or can be synthesized by known processes from the appropriate starting compounds.
• R 1 and R 5 are each as defined above.
• the hydrogenation is generally effected with a reducing agent in inert solvents, optionally with addition of acid such as mineral acids and carboxylic acids, preferably acetic acid, preferably in a temperature range of room temperature up to reflux of the solvents and in a pressure range of standard pressure to 100 bar, preferably at standard pressure or at 50-80 bar.
• acid such as mineral acids and carboxylic acids, preferably acetic acid
• a preferred reducing agent is hydrogen with palladium on activated carbon, with rhodium on activated carbon, with ruthenium on activated carbon or mixed catalysts thereof, or hydrogen with palladium on alumina or with rhodium on alumina, or hydrogen with palladium on activated carbon and platinum(IV) oxide, preference being given to hydrogen with palladium on activated carbon or with rhodium on activated carbon or hydrogen with palladium on activated carbon and platinum(IV) oxide. It is also possible to hydrogenate under pressure with hydrogen and platinum(IV) oxide alone.
• Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or concentrated acetic acid or methanol with addition of concentrated hydrochloric acid, preference being given to methanol or ethanol or concentrated acetic acid or methanol with addition of concentrated hydrochloric acid.
• alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol
• concentrated acetic acid or methanol with addition of concentrated hydrochloric acid preference being given to methanol or ethanol or concentrated acetic acid or methanol with addition of concentrated hydrochloric acid.
• R 1 is as defined above.
• the reaction is generally effected in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, preferably in a temperature range of room temperature up to reflux of the solvent at standard pressure.
• Inert solvents are, for example, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, or other solvents such as nitrobenzene, dimethylformamide, dimethylacetamide, dimethyl sulphoxide or N-methylpyrrolidone; a little water is optionally added to these solvents. Preference is given to toluene with water or to a mixture of 1,2-dimethoxyethane, dimethylformamide and water.
• Catalysts are, for example, palladium catalysts customary for Suzuki reaction conditions, preference being given to catalysts such as dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(II) acetate or bis(diphenylphosphinoferrocenyl)palladium(II) chloride, for example.
• catalysts such as dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), palladium(II) acetate or bis(diphenylphosphinoferrocenyl)palladium(II) chloride, for example.
• Additional reagents are, for example, potassium acetate, caesium, potassium or sodium carbonate, barium hydroxide, potassium tert-butoxide, caesium fluoride, potassium fluoride or potassium phosphate, or mixtures thereof, preference being given to potassium fluoride or sodium carbonate, or a mixture of potassium fluoride and potassium carbonate.
• R 1 is as defined above in the first stage with compounds of the formula (V) and in the second stage with an acid.
• the first stage reaction is effected as described for process [B]
• the second stage reaction is generally effected in inert solvents, preferably in a temperature range of room temperature to 60° C. at standard pressure.
• Inert solvents are, for example, halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane or 1,2-dichloroethane, or ethers such as tetrahydrofuran or dioxane, preference being given to methylene chloride.
• halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane or 1,2-dichloroethane
• ethers such as tetrahydrofuran or dioxane
• Bases are, for example, trifluoroacetic acid or hydrogen chloride in dioxane, preference being given to trifluoroacetic acid.
• the compounds of the formula (XVII) are known or can be prepared by reacting compounds of the formula (VIII) in the first stage with di-tert-butyl dicarboxylate and in the second stage with a base.
• the first stage reaction is generally effected in inert solvents, in the presence of a base, preferably in a temperature range of room temperature to 50° C. at standard pressure.
• Inert solvents are, for example, halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane or 1,2-dichloroethane, preference being given to methylene chloride.
• Bases are, for example, triethylamine, diisopropylethylamine or N-methylmorpholine, preference being given to triethylamine or diisopropylethylamine
• the second stage reaction is generally effected in inert solvents, in the presence of a base, preferably in a temperature range of room temperature up to reflux of the solvents at standard pressure.
• Inert solvents are, for example, halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane or 1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvent with water, preference being given to methanol or methanol with one equivalent of water, or a mixture of tetrahydrofuran and water.
• halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane or 1,2-dichloroethane
• alcohols such as methanol or ethanol
• ethers such as dieth
• Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium or potassium carbonate, or alkoxides such as potassium or sodium tert-butoxide, preference being given to lithium hydroxide or potassium tert-butoxide.
• the inventive compounds exhibit an unforeseeable, useful spectrum of pharmacological and pharmacokinetic action. They are selective antagonists of the PAR-1 receptor acting in particular as platelet aggregation inhibitors, as inhibitors of endothelial-cell activation, as inhibitors of smooth muscle cell proliferation and as inhibitors of tumour growth. For some of the disorders mentioned, for example cardiovascular disorders with high thromboembolic risk, permanent protection by PAR-1 antagonism with simultaneously simple handling of medication is of great significance.
• the PAR-1 antagonists of the present invention exhibit long-lasting action after single oral administration, i.e. an action which lasts at least 16 hours.
• the present invention further provides for the use of the inventive compounds for treatment and/or prophylaxis of disorders, preferably of thromboembolic disorders and/or thromboembolic complications.
• Thromboembolic disorders in the sense of the present invention include in particular disorders such as ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (non-STEMI), stabile angina pectoris, unstable angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty, stent implantations or aortocoronary bypass, peripheral arterial occlusion diseases, pulmonary embolisms, deep venous thromboses and renal vein thromboses, transitory ischaemic attacks and also thrombotic and thromboembolic stroke.
• STEMI ST-segment elevation myocardial infarction
• non-STEMI non-ST-segment elevation myocardial infarction
• stabile angina pectoris unstable angina pectoris
• reocclusions reocclusions and restenoses after coronary interventions
• coronary interventions such as
• the substances are therefore also suitable for prevention and treatment of cardiogenic thromboembolisms, for example brain ischaemias, stroke and systemic thromboembolisms and ischaemias, in patients with acute, intermittent or persistent cardial arrhythmias, for example atrial fibrillation, and those undergoing cardioversion, and also in patients with heart valve disorders or with intravasal objects, for example artificial heart valves, catheters, intraaortic balloon counterpulsation and pacemaker probes.
• cardiogenic thromboembolisms for example brain ischaemias, stroke and systemic thromboembolisms and ischaemias
• arrhythmias for example atrial fibrillation
• intravasal objects for example artificial heart valves, catheters, intraaortic balloon counterpulsation and pacemaker probes.
• Thromboembolic complications are also encountered in connection with microangiopathic haemolytic anaemias, extracorporeal circulation, for example haemodialysis, haemofiltration, ventricular assist devices and artificial hearts, and also heart valve prostheses.
• inventive compounds are also used to influence wound healing, for the prophylaxis and/or treatment of atherosclerotic vascular disorders and inflammatory disorders, such as rheumatic disorders of the locomotive system, coronary heart diseases, of heart failure, of hypertension, of inflammatory disorders, for example asthma, COPD, inflammatory pulmonary disorders, glomerulonephritis and inflammatory intestinal disorders, and additionally also for the prophylaxis and/or treatment of Alzheimer's disease, autoimmune disorders, Crohn's disease and ulcerative colitis.
• atherosclerotic vascular disorders and inflammatory disorders such as rheumatic disorders of the locomotive system, coronary heart diseases, of heart failure, of hypertension, of inflammatory disorders, for example asthma, COPD, inflammatory pulmonary disorders, glomerulonephritis and inflammatory intestinal disorders
• prophylaxis and/or treatment of Alzheimer's disease, autoimmune disorders, Crohn's disease and ulcerative colitis are also used to influence wound healing, for the prophylaxis and/or treatment of athe
• inventive compounds can be used to inhibit tumour growth and metastasization, for microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular disorders, and also for prevention and treatment of thromboembolic complications, for example venous thromboembolisms, for tumour patients, in particular those undergoing major surgical interventions or chemo- or radiotherapy.
• Cancers include: carcinomas (including breast cancer, hepatocellular carcinomas, lung cancer, colorectal cancer, cancer of the colon and melanomas), lymphomas (for example non-Hodgkin's lymphomas and mycosis fungoides), leukaemias, sarcomas, mesotheliomas, brain cancer (for example gliomas), germinomas (for example testicular cancer and ovarian cancer), choriocarcinomas, renal cancer, cancer of the pancreas, thyroid cancer, head and neck cancer, endometrial cancer, cancer of the cervix, cancer of the bladder, stomach cancer and multiple myeloma.
• carcinomas including breast cancer, hepatocellular carcinomas, lung cancer, colorectal cancer, cancer of the colon and melanomas
• lymphomas for example non-Hodgkin's lymphomas and mycosis fungoides
• leukaemias for example sarcomas
• mesotheliomas me
• angiogenesis vascular growth
• pulmonary disorders for example pulmonary fibrosis, pulmonary hypertension, in particular pulmonary arterial hypertension, disorders characterized by pulmonary occlusion
• arteriosclerosis plaque rupture, diabetic retinopathy and wet macular degeneration.
• the inventive compounds are suitable for the treatment of sepsis.
• Sepsis or septicaemia
• Initial symptoms of sepsis are typically unspecific (for example fever, reduced general state of health), but there may later be generalized activation of the coagulation system (“disseminated intravascular coagulation” or “consumption coagulopathy”; referred to hereinafter as “DIC”) with the formation of microthrombi in various organs and secondary bleeding complications.
• DIC dissminated intravascular coagulation
• endothelial damage with increased permeability of the vessels and diffusion of fluid and proteins into the extravasal space.
• organ dysfunction or organ failure for example kidney failure, liver failure, respiratory failure, deficits of the central nervous system and heart/circulatory failure
• this may affect any organ; the most frequently encountered organ dysfunctions and organ failures are those of the lung, the kidney, the cardiovascular system, the coagulation system, the central nervous system, the endocrine glands and the liver.
• Sepsis may be associated with an “acute respiratory distress syndrome” (referred to hereinafter as ARDS).
• ARDS may also occur independently of sepsis.
• Septic shock is the occurrence of hypotension which has to be treated and facilitates further organ damage and is associated with a worsening of the prognosis.
• Pathogens can be bacteria (gram-negative and gram-positive), fungi, viruses and/or eukaryotes.
• the site of entry or primary infection may be pneumonia, an infection of the urinary tract or peritonitis, for example.
• the infection may, but need not necessarily, be associated with bacteriaemia.
• Sepsis is defined as the presence of an infection and a “systemic inflammatory response syndrome” (referred to hereinafter as “SIRS”). SIRS occurs during infections, but also during other states such as injuries, burns, shock, operations, ischaemia, pancreatitis, reanimation or tumours.
• SIRS systemic inflammatory response syndrome
• the definition of ACCP/SCCM Consensus Conference Committee of 1992 ( Crit. Care Med. 1992, 20, 864-874) describes the symptoms required for the diagnosis of “SIRS” and measurement parameters (including a change in body temperature, increased heart rate, breathing difficulties and changes in the blood picture).
• SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference essentially maintained the criteria, but fine-tuned details (Levy et al., Crit. Care Med. 2003, 31, 1250-1256).
• DIC and SIRS may occur during sepsis, but also as a result of operations, tumour disorders, burns or other injuries.
• DIC there is massive activation of the coagulation system at the surface of damaged endothelial cells, the surfaces of foreign bodies or injured extravascular tissue.
• a secondary effect is the consumption of coagulation factors (for example factor X, prothrombin, fibrinogen) and platelets, which reduces the coagulability of the blood and may result in heavy bleeding.
• inventive compounds can also be used for preventing coagulation ex vivo, for example for preserving blood and plasma products, for cleaning/pretreating catheters and other medical aids and instruments, including extracorporeal circulation, for coating synthetic surfaces of medical aids and instruments used in vivo or ex vivo or for platelet-containing biological samples.
• the present invention further provides for the use of the inventive compounds for coating medical instruments and implants, for example catheters, prostheses, stents or artificial heart valves.
• inventive compounds may be firmly attached to the surface or, for local action, be released over a certain period of time from a carrier coating into the immediate environment.
• the present invention further provides for the use of the inventive compounds for treatment and/or prophylaxis of disorders, in particular of the abovementioned disorders.
• the present invention further provides for the use of the inventive compounds for production of a medicament for treatment and/or prophylaxis of disorders, in particular of the above-mentioned disorders.
• the present invention further provides a method for treatment and/or prophylaxis of disorders, in particular of the abovementioned disorders, using a therapeutically effective amount of an inventive compound.
• the present invention further provides medicaments comprising an inventive compound and one or more further active ingredients, in particular for treatment and/or prophylaxis of the abovementioned disorders.
• Active ingredients suitable for combinations include, by way of example and with preference:
• calcium channel blockers for example amlodipine besilate (for example Norvasc), felodipine, diltiazem, verapamil, nifedipine, nicardipine, nisoldipine and bepridil; iomerizine; statins, for example atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; cholesterol absorption inhibitors, for example ezetimibe and AZD4121; cholesteryl ester transfer protein (“CETP”) inhibitors, for example torcetrapib; low molecular weight heparins, for example dalteparin sodium, ardeparin, certoparin, enoxaparin, parnaparin, tinzaparin, reviparin and nadroparin; further anticoagulants, for example warfarin, marcumar, fondaparinux; antiarrhythmics
• Antibiotic therapy various antibiotics or antifungal medicament combinations are suitable, either as calculated therapy (before the microbial assessment has been made) or as specific therapy; fluid therapy, for example crystalloid or colloidal fluids; vasopressors, for example norepinephrine, dopamine or vasopressin; inotropic therapy, for example dobutamine; corticosteroids, for example hydrocortisone, or fludrocortisone; recombinant human activated protein C, Xigris; blood products, for example erythrocyte concentrates, platelet concentrates, erythropoietin or fresh frozen plasma; assisted ventilation in sepsis-induced acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), for example permissive hypercapnia, low tidal volumes; sedation: for example diazepam, lorazepam, midazolam or propofol.
• fluid therapy for example crystalloid or colloidal fluids
• vasopressors for example no
• Opioids for example fentanyl, hydromorphone, morphine, meperidine or remifentanil.
• NSAIDs for example ketorolac, ibuprofen or acetaminophen.
• Neuromuscular blockade for example pancuronium; glucose control, for example insulin, glucose; renal replacement therapies, for example continuous veno-venous haemofiltration or intermittent haemodialysis.
• Low-dose dopamine for renal protection for example; anticoagulants, for example for thrombosis prophylaxis or for renal replacement therapies, for example unfractionated heparins, low molecular weight heparins, heparinoids, hirudin, bivalirudin or argatroban; bicarbonate therapy; stress ulcer prophylaxis, for example H2 receptor inhibitors, antacids.
• anticoagulants for example for thrombosis prophylaxis or for renal replacement therapies, for example unfractionated heparins, low molecular weight heparins, heparinoids, hirudin, bivalirudin or argatroban
• bicarbonate therapy for example stress ulcer prophylaxis, for example H2 receptor inhibitors, antacids.
• Medicaments for proliferative disorders uracil, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulphan, carmustine, lomustine, streptozocin, dacarbazine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, paclitaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide, 17.alpha.-ethyny
• the present invention further provides a method for prevention of blood coagulation in vitro, in particular in banked blood or biological samples containing platelets, which is characterized in that an anticoagulatory amount of the inventive compound is added.
• inventive compounds can act systemically and/or locally.
• they can be administered in a suitable way, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route or as implant or stent.
• inventive compounds can be administered in administration forms suitable for these administration routes.
• Suitable administration forms for oral administration are those which function according to the prior art and deliver the inventive compounds rapidly and/or in modified fashion, and which contain the inventive compounds in crystalline and/or amorphized and/or dissolved form, for example, tablets (uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the inventive compound), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
• Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
• Oral administration is preferred.
• Suitable for the other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents.
• pharmaceutical forms for inhalation inter alia powder inhalers, nebulizers
• nasal drops solutions or sprays
• tablets for lingual, sublingual or buccal administration films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems
• the inventive compounds can be converted to the administration forms mentioned. This can be done 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 dispersants 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), colours (e.g. inorganic pigments, for example, iron oxides) and masking flavours and/or odours.
• carriers for example microcrystalline cellulose, lactose, mannitol
• solvents e.g. liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium do
• the present invention further provides medicaments comprising at least one inventive compound, preferably together with one or more inert, non-toxic, pharmaceutically acceptable excipients, and their use for the purposes mentioned above.
• parenteral administration it has generally been found to be advantageous to administer amounts of about 5 to 250 mg every 24 hours to achieve effective results. In the case of oral administration the amount is about 5 to 100 mg every 24 hours.
• MS instrument type Micromass ZQ
• HPLC instrument type HP 1100 Series
• UV DAD column: Phenomenex Gemini 3 ⁇ , 30 mm ⁇ 3.0 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
• flow rate 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.
• Instrument Micromass QuattroPremier with Waters HPLC Acquity; column: Thermo Hypersil GOLD 1.9 ⁇ , 50 mm ⁇ 1 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 ⁇ 1.5 min 10% A ⁇ 2.2 min 10% A; oven: 50° C.; flow rate: 0.33 ml/min; UV detection: 210 nm.
• MS instrument type Micromass ZQ
• HPLC instrument type Waters Alliance 2795
• 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
• flow rate 2 ml/min
• UV detection 210 nm.
• MS instrument type Waters ZQ
• HPLC instrument type Waters Alliance 2795
• 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
• flow rate 2 ml/min
• oven 40° C.
• UV detection 210 nm.
• Instrument Micromass Platform LCZ with HPLC Agilent Series 1100; column: Thermo HyPURITY Aquastar 3 ⁇ 50 mm ⁇ 2.1 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 rate: 0.8 ml/min; UV detection: 210 nm.
• MS instrument type Waters ZQ; HPLC instrument type: Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3 ⁇ LE 20 mm ⁇ 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 ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A, oven: 55° C.; flow rate: 2 ml/min; UV detection: 210 nm.
• Instrument Micromass GCT, GC6890; column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant flow rate with helium: 0.88 ml/min; oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min ⁇ 310° C. (hold for 3 min).
• the microwave reactor used was a “single mode” instrument of the EmrysTM Optimizer type.
• a mixture of the appropriate bromopyridine in toluene (1.8 ml/mmol) is admixed under argon at RT with tetrakis(triphenylphosphine)palladium (0.02 eq.), with a solution of the appropriate arylboronic acid (1.2 eq.) in ethanol (0.5 ml/mmol) and with a solution of potassium fluoride (2.0 eq.) in water (0.2 ml/mmol).
• the reaction mixture is stirred under reflux for several hours until the conversion is substantially complete.
• a solution of the pyridine in ethanol (9 ml/mmol) is admixed under argon with palladium on activated carbon (moistened with approx. 50% water, 0.3 g/mmol), and the mixture is hydrogenated at 60° C. in a 50 bar hydrogen atmosphere overnight.
• the catalyst is then filtered off through a filter layer and washed repeatedly with ethanol. The combined filtrates are concentrated under reduced pressure.
• potassium tert-butoxide (10 eq.) is added to a solution of the appropriate methyl ester (1.0 eq.) in methanol (35-40 ml/mmol). The mixture is stirred at 60° C. overnight. If the conversion is incomplete, water (1.0 eq.) is added and the mixture is stirred at 60° C. until the conversion is complete.
• the methanol is removed under reduced pressure, the residue is admixed with water and the mixture is acidified (pH 1) with aqueous 1 N hydrochloric acid solution. The mixture is extracted with ethyl acetate and the organic phase is dried with magnesium sulphate, filtered and concentrated under reduced pressure.
• a solution of the pyridine in concentrated acetic acid (about 35 ml/mmol) is hydrogenated in a flow hydrogenation apparatus (“H-Cube” from ThalesNano, Budapest, Hungary) under a hydrogen atmosphere (conditions: 10% Pd/C catalyst, “controlled” mode, 60 bar, 0.5 ml/min, 85° C.). Removal of the solvent on a rotary evaporator gives the corresponding crude product which is optionally purified by means of preparative HPLC.
• a solution of the appropriate piperidine-3-carboxylic acid in dimethylformamide (10-20 ml/mmol) is admixed under argon at RT with HATU (1.2 eq.), N,N-diisopropylethylamine (2.2 eq.) and the appropriate N′-hydroxyimidamide (1.1 eq.).
• the reaction mixture is stirred at RT until the intermediate has been formed completely and then stirred further at 120° C. until the desired product is formed from this intermediate.
• the reaction mixture is then purified by means of preparative HPLC.
• a solution of the appropriate piperidine-3-carboxylic acid in dimethylformamide (10-20 ml/mmol) is admixed under argon at RT with HATU (1.2 eq.), N,N-diisopropylethylamine (2.2 eq.) and the appropriate alkyl N-hydroxyimidocarbamate (1.1 eq.).
• the reaction mixture is stirred at RT until the formation of the intermediate is complete and then stirred further at 120° C. until the desired product is formed from this intermediate.
• the reaction mixture is then purified by means of preparative HPLC.

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