Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • 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

Definitions

• the invention relates to substituted oxopyridine derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular vascular disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications.
• Haemostasis is a protective mechanism of the organism, which helps to "seal" leaking damages in the blood vessel wall quickly and reliably. Thus, excessive loss of blood can often be avoided or kept to a minimum.
• hemostasis is conducted mainly by activation and aggregation of platelets and activation the coagulation system, which consists of an enzymatic “waterfall” cascade leading one after another to the activation of the next coagulation factor until thrombin is formed, which leads to the generation of insoluble fibrin, which is an important part of the clot.
• a central component of the transition from initiation to amplification of coagulation and thereby thrombus propagation is factor XIa: in positive feedback loops, thrombin activates not only factor V and factor VIII, but also factor XI to factor XIa, which in turn converts factor IX into factor IXa, which in turn in a factor IXa/factor Villa complex generates factor Xa and finally to large amounts of thrombin, resulting in strong thrombus growth and stabilization of the thrombus. This is supported by TAFIa and FXIIIa, which are activated by thrombin as well and lead to inhibition of clot lysis and further clot stabilisation.
• the coagulation system can be activated particularly on negatively charged surfaces, which include not only surface structures of foreign cells (e.g. bacteria) but also artificial surfaces such as vascular prostheses, stents and extracoporeal circulation.
• factor XII FXII
• factor Xlla factor XIIa
• factor Xlla also activates bound plasma prokallikrein to plasma kallikrein (PK) which, in a potentiation loop, firstly leads to further factor XII activation, overall resulting in amplification of the initiation of this intrinsic part of the coagulation cascade.
• PK plasma kallikrein
• Uncontrolled activation of the coagulation system or defective inhibition of the activation processes may lead to the formation of local thrombi or emboli in vessels (e.g. arteries, veins, lymph vessels) or in organ cavities (e.g. cardiac atrium).
• vessel e.g. arteries, veins, lymph vessels
• organ cavities e.g. cardiac atrium
• systemic hypercoagulability may lead to system-wide formation of microthrombi and finally to a consumption coagulopathy in the context of a disseminated intravasal coagulation.
• Thromboembolic complications may also occur in extracorporeal circulatory systems, such as haemodialysis, and also in vascular prostheses or prosthetic heart valves and stents.
• coagulation and platelet activation occur owing to either systemic factors such as hyperlipidaemia, diabetes, inflammation, infection or smoking, or to changes in blood flow with stasis, for example in in diseased leg veins or in atrial fibrillation, or owing to pathological changes in vessel walls, for example endothelial dysfunctions or atherosclerosis.
• This unwanted and excessive activation of coagulation may, by formation of fibrin- and platelet-rich thrombi, lead to thromboembolic disorders and thrombotic complications with often life-threatening events. Inflammation processes may also be involved by triggering the coagulation system.
• thrombin is known to activate inflammatory pathways, as well.
• thromboembolic disorders are still the most frequent cause of morbidity and mortality in most industrialized countries.
• anticoagulants known from the prior art that is to say substances for inhibiting or preventing blood coagulation, have various disadvantages. Accordingly, in practice, efficient treatment methods or the prophylaxis of thrombotic/thromboembolic disorders is found to be difficult and unsatisfactory.
• heparin In the therapy and prophylaxis of thromboembolic disorders, use is made, firstly, of heparin which is administered parenterally or subcutaneously. Because of more favourable pharmacokinetic properties, preference is these days increasingly given to low -molecular-weight heparin; however, the known disadvantages described herein below encountered in heparin therapy cannot be avoided either in this manner. Thus, heparin is orally ineffective and has only a comparatively short half-life. In addition, there is a high risk of bleeding, there may in particular be cerebral haemorrhages and bleeding in the gastrointestinal tract, and there may be thrombopaenia, alopecia medicomentosa or osteoporosis.
• a second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3- indanediones and in particular compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives which non-selectively inhibit the synthesis of various products of vitamin In dependent coagulation factors in the liver. Owing to the mechanism of action, the onset of action is only very slow (latency to the onset of action 36 to 48 hours). The compounds can be administered orally; however, owing to the high risk of bleeding and the narrow therapeutic index complicated individual adjustment and monitoring of the patient are required. In addition, other side-effects such as gastrointestinal problems, hair loss and skin necroses have been described.
• Non-vitamin K dependent oral anticoagulantion are in clinical use, and have demonstrated their effectiveness in various studies. However, taking these medicaments can also lead to bleeding complications, particularly in predisposed patients.
• the therapeutic window is of central importance:
• the interval between the therapeutically active dose for coagulation inhibition and the dose where bleeding may occur should be as large as possible so that maximum therapeutic activity is achieved at a minimum risk profile.
• factor XIa inhibitors antibodies as factor XIa inhibitors
• factor XIa knock-out animal models the antithrombotic effect with small/no prolongation of bleeding time or extension of blood volume was confirmed.
• elevated factor XIa concentrations were associated with an increased thrombotic event rate.
• factor XI deficiency (haemophilia C) did not lead to spontaneous bleeding and was apparent only in the course of surgical operations and traumata, but did show protection with respect to certain thromboembolic events.
• WO 2006/030032 describes inter alia substituted pyridinones as allosteric modulators of the mGluR2 receptor, and WO 2008/079787 describes substituted pyridin-2-ones and their use as glucokinase activators.
• WO 2014/154794, WO 2014/160592, WO 2015/011087, WO 2015/063093, WO 2016/046158, WO 2016/046157, WO 2016/046159, WO 2016/046164, WO 2016/046166, WO 2016/046156, WO 2017/005725 and WO 2017/037051 describe substituted pyridin-2-ones and their use as factor XIa inhibitors.
• the invention provides compounds of the formula
• R 1 represents methyl, ethyl, difluoromethyl or trifluoromethyl
• R 2 represents hydrogen, methyl, difluoromethyl or trifluoromethyl
• R 1 and R 2 together with the carbon atoms to which they are attached form a cyclobutyl ring
• R 3 represents methyl, ethyl or n-propyl
• methyl may be substituted with one substituent selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, tetrahydrofiiran-2-yl, tetrahydro-2H- pyran-2-yl, tetrahydro-2H-pyran-4-yl and l,4-dioxan-2-yl,
• oxetan-2-yl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-2-yl and 1,4-dioxan- 2-yl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine and methyl,
• R 9 represents methyl, ethyl, iso-propyl, cyclopropyl, difluoromethyl or trifluoromethyl,
• R 10 represents methyl or difluoromethyl
• ethyl may be substituted with one substituent selected from the group consisting of methoxy, ethoxy, iso-propoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, 2,2- difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyloxy and cyclobutyloxy,
• cyclopropyloxy and cyclobutyloxy may be substituted with one substituent selected from the group consisting of fluorine and methyl,
• R 4 represents hydrogen
• R 5 represents a group of the formula
• R 11 represents hydrogen or fluorine
• R 12 represents methyl, difluoromethyl or trifluoromethyl
• R 13 represents methyl, difluoromethyl or trifluoromethyl
• R 14 represents hydrogen or methyl
• R 15 represents hydrogen or methyl
• R 16 represents hydrogen or methyl
• R 17 represents hydrogen or methyl
• R 6 , R 7 and R 8 represent the following:
• R 6 represents hydrogen, fluorine or chlorine
• R 7 represents hydrogen
• R 8 represents hydrogen
• R 6 represents hydrogen
• R 7 represents fluorine or chlorine
• R 8 represents hydrogen
• R 6 represents hydrogen
• R 7 represents hydrogen
• R 8 represents fluorine
• Compounds according to the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, and also the compounds encompassed by formula (I) and specified hereinafter as working example(s), and the salts, solvates and solvates of the salts thereof, to the extent that the compounds encompassed by formula (I) and specified hereinafter are not already salts, solvates and solvates of the salts.
• inventive compounds may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else, if appropriate, of conformational isomers (enantiomers and/or diastereomers, including those in the case of rotamers and atropisomers).
• the present invention therefore encompasses the enantiomers and diastereomers, and the respective mixtures thereof.
• the stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this, especially HPLC chromatography on an achiral or chiral phase.
• the present invention encompasses all the tautomeric forms.
• the term“enantiomerically pure“ is understood to mean that the compound in question with respect to the absolute configuration of the chiral centre is present in an enantiomeric excess of more than 95%, preferably more than 97%.
• the present invention also encompasses all suitable isotopic variants of the compounds according to the invention.
• An isotopic variant of an inventive compound is understood here as meaning a compound in which at least one atom within the inventive compound has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
• isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 129 I and 131 I.
• Particular isotopic variants of a compound according to the invention may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; due to comparatively easy preparability and detectability, especially compounds labelled with 3 H or 14 C isotopes are suitable for this purpose.
• the incorporation of isotopes, for example of deuterium may lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the inventive compounds may therefore in some cases also constitute a preferred embodiment of the present invention.
• Isotopic variants of the compounds according to the invention can be prepared by the processes known to those skilled in the art, for example by the methods described further below and the procedures described in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds.
• Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention.
• the invention also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention.
• Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example 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.
• Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N- methylmorpholine, arginine, lysine, ethylenediamine, '-mcthylpipcridinc and choline.
• alkali metal salts e.g. sodium and potassium salts
• alkaline earth metal salts e.g. calcium and magnesium salts
• Solvates in the context of the invention are described as those forms of the inventive compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water.
• the present invention additionally also encompasses prodrugs of the inventive compounds.
• prodrugs encompasses compounds which for their part may be biologically active or inactive but are converted during their residence time in the body into compounds according to the invention (for example by metabolism or hydrolysis).
• treatment includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states.
• therapy is understood here to be synonymous with the term “treatment”.
• prevention means prevention, prophylaxis and “preclusion” are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or advancement of such states and/or the symptoms of such states.
• the treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.
• the end point of the line marked by * in each case does not represent a carbon atom or a CTT group, but is part of the bond to the atom to which the group is attached.
• the end point of the line marked by # in each case does not represent a carbon atom or a CTT group, but is part of the bond to the atom to which R 5 is attached.
• R 1 represents methyl, ethyl or trifluoromethyl
• R 2 represents hydrogen or methyl
• R 1 and R 2 together with the carbon atoms to which they are attached form a cyclobutyl ring
• R 3 represents methyl, ethyl or n-propyl, where methyl may be substituted with one substituent selected from the group consisting of cyclobutyl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-2-yl and l,4-dioxan-2-yl,
• tetrahydrofuran-2-yl may be substituted by 1 to 2 substituents methyl, or
• R 9 represents methyl, cyclopropyl, difluoromethyl or trifluoromethyl
• R 10 represents methyl or difluoromethyl
• ethyl may be substituted with one substituent selected from the group consisting of methoxy, iso-propoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, cyclopropyloxy and cyclobutyloxy,
• cyclopropyloxy and cyclobutyloxy may be substituted with one substituent selected from the group consisting of fluorine and methyl,
• R 4 represents hydrogen
• R 5 represents a group of the formula
• R 1 1 represents hydrogen or fluorine
• R 12 represents difluoromethyl or trifluoromethyl
• R 13 represents methyl
• R 14 represents hydrogen or methyl
• R 15 represents hydrogen or methyl
• R 16 represents hydrogen
• R 17 represents hydrogen
• R 6 , R 7 and R 8 represent the following:
• R 6 represents hydrogen, fluorine or chlorine
• R 7 represents hydrogen
• R 8 represents hydrogen
• R 1 and R 2 together with the carbon atoms to which they are attached form a cyclobutyl ring
• R 3 represents methyl, ethyl or n-propyl
• methyl may be substituted with one substituent selected from the group consisting of cyclobutyl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-2-yl and l,4-dioxan-2-yl,
• tetrahydrofuran-2-yl may be substituted by 1 to 2 substituents methyl, or
• R 9 represents methyl, cyclopropyl, difluoromethyl or trifluoromethyl
• R 10 represents methyl or difluoromethyl
• ethyl may be substituted with one substituent selected from the group consisting of methoxy, iso-propoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, cyclopropyloxy and cyclobutyloxy,
• cyclopropyloxy and cyclobutyloxy may be substituted with one substituent selected from the group consisting of fluorine and methyl,
• R 4 represents hydrogen
• R 5 represents a group of the formula # is the attachment site to the nitrogen atom
• R 1 1 represents hydrogen or fluorine
• R 12 represents difhioromethyl or trifluoromethyl
• R 13 represents methyl
• R 15 represents hydrogen or methyl
• R 16 represents hydrogen
• R 6 , R 7 and R 8 represent the following:
• R 6 represents hydrogen or fluorine
• R 7 represents hydrogen
• R 8 represents hydrogen
• R 1 represents methyl or trifluoromethyl
• R 2 represents hydrogen
• R 1 and R 2 together with the carbon atoms to which they are attached form a cyclobutyl ring
• R 3 represents methyl or ethyl, where methyl is substituted with one substituent selected from the group consisting of tetrahydro-2H-pyran-2-yl and l,4-dioxan-2-yl,
• R 9 represents methyl
• R 10 represents methyl or difluoromethyl
• ethyl is substituted with one substituent selected from the group consisting of methoxy, iso-propoxy, tert-butoxy, difluoromethoxy and cyclopropyloxy,
• cyclopropyloxy may be substituted with one substituent selected from the group consisting of fluorine and methyl,
• R represents hydrogen
• R represents a group of the formula
• R 11 represents hydrogen or fluorine
• R 13 represents methyl
• R 15 represents hydrogen or methyl
• R 16 represents hydrogen
• R 6 , R 7 and R 8 represent the following:
• R 6 represents hydrogen or fluorine
• R 7 represents hydrogen
• R 8 represents hydrogen
• R 1 represents methyl or trifluoromethyl
• R 2 represents hydrogen
• R 3 represents methyl
• R 9 represents methyl
• R 10 represents methyl or difluoromethyl
• R 4 represents hydrogen
• R 5 represents a group of the formula
• R 11 represents hydrogen
• R 6 , R 7 and R 8 represent the following:
• R 6 represents hydrogen or fluorine
• R 7 represents hydrogen
• R 8 represents hydrogen
• R 6 , R 7 and R 8 represent the following:
• R 6 represents hydrogen or fluorine
• R 7 represents hydrogen
• R 8 represents hydrogen
• R 6 , R 7 and R 8 represent the following:
• R 6 represents hydrogen
• R 7 represents hydrogen
• R 8 represents hydrogen
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.
• the invention further provides a method for preparing compounds of the formula (I), or salts thereof, solvates thereof or solvates of the salts thereof, wherein
• R 1 , R 2 , R 3 , R 6 , R 7 and R 8 are as defined above, are reacted with compounds of the formula
• R 4 and R 5 are as defined above,
• R 1 , R 2 , R 6 , R 7 and R 8 are as defined above,
• X 1 represents bromine, iodine or trifluoromethane-sulfonyloxy
• reaction according to process [A] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from -20°C to 80°C at atmospheric pressure.
• reaction can also be carried out without a solvent only in one base if the base is a liquid at RT.
• Suitable dehydrating agents are, for example, carbodiimides such as A, A -diethyl- A A dipropyl-, A, ’-diisopropyl-, AA’-dicyclohexylcarbodiimide, A-/ -dimethylaminoisopropyl/-A- ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), A- cyclohexylcarbodiimide-A‘-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl- 1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-e
• Bases are, for example, organic bases such as trialkylamines, for example triethylamine, N- methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamin, or pyridine, preference is given to condensation with diisopropylethylamine or pyridine.
• organic bases such as trialkylamines, for example triethylamine, N- methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamin, or pyridine, preference is given to condensation with diisopropylethylamine or pyridine.
• Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, or other solvents such as 1,4-dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile, or mixtures of the solvents, preference being given to N,N-dimethylformamide or tetrahydrofuran.
• halogenated hydrocarbons such as dichloromethane or trichloromethane
• hydrocarbons such as benzene or toluene
• other solvents such as 1,4-dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile,
• reaction according to process [B] is generally carried out in inert solvents, in the presence of a chlorination agent, preferably in a temperature range from -20°C to 80°C at atmospheric pressure.
• Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, or other solvents such as 1,4-dioxane, diethyl ether, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide, or mixtures of the solvents, preference being given to dichloromethane.
• halogenated hydrocarbons such as dichloromethane or trichloromethane
• hydrocarbons such as benzene or toluene
• other solvents such as 1,4-dioxane, diethyl ether, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide, or mixtures of the solvents, preference being given to dichloromethane.
• Chlorination agents are, for example, I -ch 1 o ro - W 2 -t ri m c th yl p ro p - 1 -c n - 1 -am i n c . oxalyl chloride, sulfurous dichloride, preference being given to I -chloro-/VJV.2-trimethylprop- 1 -en- 1 -amine.
• reaction according to process [C] is generally carried out in inert solvents, preferably in a temperature range from room temperature to reflux of the solvents at atmospheric pressure.
• Bases are, for example, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate, or potassium tert-butoxide or sodium tert-butoxide, sodium hydride or a mixture of these bases or a mixture of sodium hydride and lithium bromide, or organic bases such as 1,1,3,3-tetramethylguanidine or 2-tert-butylimino-2-diethylamino-l,3-dimethylperhydro-l,3,2- diazaphosphorine (BEMP), preference is given to potassium carbonate or sodium hydride or 1,1,3,3- tetramethylguanidine .
• alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide
• alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate, or potassium tert-butoxide or sodium tert-butoxid
• Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols such as methanol, ethanol or 2-propanol, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, or other solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, pyridine or acetone, or mixtures of solvents, or mixtures of solvents with water, preference is given to N,N-dimethylformamide or to a mixture of acetone and 2 -propanol.
• halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane
• the compounds of the formula (III) are known or can be synthesized from the corresponding starting compounds by known processes.
• the compounds of the formula (V) are known, can be synthesized from the corresponding starting compounds by known processes or can be prepared analogously to the processes described in the Examples section.
• the compounds of the formula (II) are known or can be prepared by reacting
• R 1 , R 2 , R 3 , R 6 , R 7 and R 8 are each as defined above and
• R 18 represents tert-butyl
• R 1 , R 2 , R 3 , R 6 , R 7 and R 8 are each as defined above and
• R 18 represents methyl, ethyl, tert-butyl or benzyl
• reaction according to process [D] is generally carried out in inert solvents, preferably in a temperature range from 0°C to 60°C at atmospheric pressure.
• Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, or ethers such as tetrahydrofuran or 1,4-dioxane, preference being given to dichloromethane.
• halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane
• ethers such as tetrahydrofuran or 1,4-dioxane, preference being given to dichloromethane.
• Acids are, for example, trifluoroacetic acid or hydrogen chloride in 1,4-dioxane, preference being given to trifluoroacetic acid.
• reaction according to process [E] is generally carried out in solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
• Inert solvents are, for example, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert-butyl ether, 1, 2 -dimethoxy ethane, 1,4-dioxane or tetrahydrofuran, or mixtures of solvents, or mixtures of solvents with water, preference being given to a mixture of tetrahydrofuran and water.
• Bases are, for example, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate, preference being given to lithium hydroxide.
• R 1 , R 2 , R 6 , R 7 and R 8 are each as defined above and
• R 18 represents tert-butyl
• R 3 is as defined above and
• X 2 represents chlorine, bromine, iodine or trifluoromethanesulfonyloxy.
• the reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from -78°C to room temperature at atmospheric pressure.
• Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2- dimethoxyethane, 1,4-dioxane or tetrahydrofuran, or mixtures of solvents, or mixtures of solvent with water, preference is given to tetrahydrofuran.
• ethers such as diethyl ether, methyl tert-butyl ether, 1,2- dimethoxyethane, 1,4-dioxane or tetrahydrofuran, or mixtures of solvents, or mixtures of solvent with water, preference is given to tetrahydrofuran.
• Bases are, for example, potassium tert-butoxide or sodium tert-butoxide, sodium hydride, n- butyllithium, lithium bis(trimethylsilyl)amide or sodium bis(trimethylsilyl)amide, preference is given to lithium bis(trimethylsilyl)amide or sodium bis(trimethylsilyl)amide.
• the compounds of the formula (VIII) are known or can be synthesized from the corresponding starting compounds by known processes.
• R 1 , R 2 , R 6 , R 7 and R 8 are as defined above,
• X 3 represents chlorine, bromine, iodine, methane sulfonyloxy or trifluoromethane-sulfonyloxy and
• R 18 represents tert-butyl
• reaction is carried out as described for process [C].
• the compounds of the formula (IX) are known or can be synthesized from the corresponding starting compounds by known processes.
• the compounds of the formula (VI) can be prepared by reacting compounds of the formula (IV) with compounds of the formula
• X 4 represents chlorine, bromine, iodine, methane sulfonyloxy or trifluoromethane-sulfonyloxy and
• R 18 represents methyl, ethyl, tert-butyl or benzyl.
• reaction is carried out as described for process [C].
• the compounds of the formula (X) are known, can be synthesized from the corresponding starting compounds by known processes or can be prepared analogously to the processes described in the Examples section.
• the compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula
• R 1 , R 2 , R 6 , R 7 and R 8 are as defined above,
• the reaction is generally carried out in inert solvents or without solvents, preferably in a temperature range of from 80°C to 120°C at atmospheric pressure.
• Inert solvents are, for example, hydrocarbons such as benzene, or alcohols such as methanol, ethanol or 1 -butanol, or other solvents such as nitromethane, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile, or a mixture of the solvents, preference is given to N,N-dimethylformamide or 1 -butanol.
• hydrocarbons such as benzene
• alcohols such as methanol, ethanol or 1 -butanol
• other solvents such as nitromethane, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile, or a mixture of the solvents, preference is given to N,N-dimethylformamide or 1 -butanol.
• Acids are, for example, 4-toluenesulfonic acid monohydrate, formic acid, acetic acid, trifluoroacetic acid, preference is given to acetic acid and 4-toluenesulfonic acid monohydrate.
• Bases are, for example, potassium tert-butoxide or sodium / -butoxide or sodium hydride, preference is given to sodium hydride.
• the compounds of the formula (XI) are known or can be prepared by reacting compounds of the formula
• R 1 , R 2 , R 6 , R 7 and R 8 are as defined above,
• the reaction is generally carried out in inert and degassed solvents, preferably within a temperature range from 80°C to 150°C at atmospheric pressure.
• Bases are, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, organic bases such as sodium pivalate, potassium pivalate, caesium pivalate, sodium acetate, potassium acetate, caesium acetate, preference is given to potassium pivalate or potassium acetate.
• Catalysts are, for example, palladium catalysts customary for CH-activation conditions, such as dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate/triscyclohexylphosphine, bis(tri-fert-butylphosphine)palladium(0), tris(dibenzylidene- acetone)dipalladium, bis(diphenylphosphaneferrocenyl)palladium(II) chloride, l,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene( 1 ,4-naphthoquinone)palladium dimer, allyl(chloro)( 1,3 - dimesityl-1, 3-dihydro-2H-imidazol-2-ylidene)palladium, palladium(
• Inert solvents are, for example, ethers such as 1,4-dioxane, tetrahydrofuran or 1, 2 -dimethoxy ethane, hydrocarbons such as benzene, xylene or toluene, or carboxamides such as N,N-dimethylformamide or N,N-dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, or mixtures of the solvents with water, preference is given to N,N-dimethylformamide or N,N-dimethylacetamide.
• the compounds of the formula (XI) can be prepared by reacting compounds of the formula (XI)
• R 1 , R 2 , R 6 , R 7 and R 8 are as defined above,
• the reaction is generally carried out in inert solvents, preferably within a temperature range from room temperature to 150°C at atmospheric pressure.
• Catalysts are, for example, palladium catalysts customary for Suzuki reaction conditions, preference being given to catalysts such as dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(O), bis(tri-/ -biitylphosphine)palladiiim(0).
• Bases are, for example, alkali metal carbonates such as caesium carbonate, potassium carbonate or sodium carbonate, alkali metal bicarbonates such as, sodium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or potassium acetate, potassium /er/-butoxide or potassium phosphate, where these may be present in aqueous solution, preference being given to an aqueous sodium bicarbonate solution or potassium acetate.
• alkali metal carbonates such as caesium carbonate, potassium carbonate or sodium carbonate
• alkali metal bicarbonates such as, sodium bicarbonate
• alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or potassium acetate, potassium /er/-butoxide or potassium phosphate, where these may be present in aqueous solution, preference being given to an aqueous sodium bicarbonate solution or potassium acetate.
• Inert solvents are, for example, ethers such as 1,4-dioxane, tetrahydrofuran or 1, 2 -dimethoxy ethane, hydrocarbons such as benzene, xylene or toluene, or carboxamides such as N,N-dimethylformamide or N,N-dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, or N-methylpyrrolidone or acetonitrile, or mixtures of the solvents with alcohols such as methanol or ethanol and/or water, preference is given to N,N-dimethylformamide.
• ethers such as 1,4-dioxane, tetrahydrofuran or 1, 2 -dimethoxy ethane
• hydrocarbons such as benzene, xylene or toluene
• carboxamides such as N,N-dimethylformamide or N,N-dimethylace
• R 1 , R 2 , R 6 , R 7 and R 8 are as defined above,
• the reaction is carried out in the presence of (tributylphosphoranylidene)-acetonitrile, in inert solvents such as benzene, xylene or toluene, preference is given to toluene, optionally in a microwave, preferably within a temperature range from 80°C to 160°C at atmospheric pressure to 3 bar or higher than 3 bar using a microwave,
• the reaction is carried out in the presence of an ester of the azodicarboxylic acid such as diisopropyl azodicarboxylate (DIAD) and organophosphorus compounds such as triphenylphosphine, in inert solvents such as tetrahydrofuran, 1 ,4-dioxane or dichloromethane, within a temperature range of 0°C to room temperature at atmospheric pressure.
• an ester of the azodicarboxylic acid such as diisopropyl azodicarboxylate (DIAD) and organophosphorus compounds such as triphenylphosphine
• inert solvents such as tetrahydrofuran, 1 ,4-dioxane or dichloromethane
• R 1 , R 2 , R 6 , R 7 and R 8 are as defined above,
• reaction is carried out as described for the reaction of compounds of the formula (XIV) with compounds of the formula (XV) .
• the compounds of the formula (XVI) are known, can be synthesized from the corresponding starting compounds by known processes or can be prepared analogously to the processes described in the Examples section.
• the compounds according to the invention have an unforeseeable useful pharmacological activity spectrum and good pharmacokinetic properties. They are compounds that influence the proteolytic activity of the serine protease factor XIa (FXIa).
• FXIa serine protease factor XIa
• the compounds according to the invention inhibit the enzymatic cleavage of FXIa-substrates, such as factor IX (FIX), which have essential roles in the activation of blood coagulation, in the aggregation of blood platelets via PAR-1 activation of the platelets, and in inflammatory processes, which particularly involve an increase in vascular permeability.
• FXIa-substrates such as factor IX (FIX)
• the present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular vascular disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications.
• Factor XIa is an important enzyme in the context of coagulation, which can be activated by both thrombin and factor Xlla (FXIIa), and is therefore involved in two essential processes of coagulation. It is a central component of the transition from initiation to amplification of the coagulation and propagation of the clot: in positive feedback loops, thrombin activates, in addition to factor V and factor VIII, also factor XI to factor XIa, whereby factor IX is converted into factor IXa, and, via the factor IXa/factor Villa complex generated in this manner, factor Xa and subsequently thrombin are formed, leading to strong thrombus growth and stabilization of the thrombus.
• FXIa Factor XIa
• factor XIa is an important component for the intrinsic initiation of coagulation:
• tissue factor (TF) in addition to the stimulation via tissue factor (TF) in the extrinsic pathway, the coagulation system can be activated also particularly on negatively charged surfaces, which include not only surface structures of foreign cells (e.g. bacteria) but also artificial surfaces such as vascular prostheses, stents and parts of extracorporeal circulation systems.
• factor XII FXII
• the compounds according to the invention are suitable for the treatment and/or prophylaxis of disorders or complications which may arise from the formation of clots.
• the "thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications” include disorders and complications, which occur in the arterial, the venous vascular system and the lymphatic system, which can be treated with the compounds according to the invention.
• ACS acute coronary syndrome
• STEMI myocardial infarction with ST segment elevation
• non-STEMI stable angina pectoris
• unstable angina pectoris unstable angina pectoris
• stent thrombosis reocclusions and restenoses after coronary interventions
• coronary interventions such as angioplasty, stent implantation or aortocoronary bypass
• disorders in the cerebrovascular arteries such as transitory ischaemic attacks (TIA)
• non-cardioembolic strokes such as lacunar stroke
• strokes due to large or small artery diseases or strokes due to undetermined cause
• cryptogenic strokes embolic strokes, embolic strokes of undetermined source, or events of thrombotic and/or thromboembolic origin leading to stroke or TIA
• embolic strokes embolic strokes of undetermined source, or events of thrombotic
• this includes thrombotic or thromboembolic disorders in particular in veins of the extremities, kidneys, mesenterium, liver, brain and eye, leading to pulmonary embolisms, venous thromboembolisms and/or venous thrombosis.
• Stimulation of the coagulation system may occur by various causes or associated disorders.
• the coagulation system can be highly activated, and there may be thrombotic complications, in particular venous thromboses.
• the compounds according to the invention are therefore suitable for the prophylaxis of thrombosis in the context of surgical interventions in patients suffering from cancer.
• the compounds according to the invention are therefore also suitable for the prophylaxis of thrombosis in patients having an activated coagulation system, for example in the situations described above.
• inventive compounds are therefore also suitable for the prevention and treatment of cardiogenic thromboembolisms, for example brain ischaemias, stroke and systemic thromboembolisms and ischaemias, in patients with acute, intermittent or persistent cardiac arrhythmias, for example atrial fibrillation, and in patients undergoing cardioversion, and also in patients with heart valve disorders or with artificial heart valves.
• cardiogenic thromboembolisms for example brain ischaemias, stroke and systemic thromboembolisms and ischaemias
• acute, intermittent or persistent cardiac arrhythmias for example atrial fibrillation
• atrial fibrillation for example atrial fibrillation
• cardioversion for example atrial fibrillation
• inventive compounds are suitable for the treatment and prevention of disseminated intravascular coagulation (DIC) which may occur in connection with sepsis inter alia, but also owing to surgical interventions, neoplastic disorders, bums or other injuries and may lead to severe organ damage through microthrombosis.
• DIC disseminated intravascular coagulation
• Thromboembolic complications furthermore occur in microangiopathic haemolytical anaemias and by blood coming into contact with artificial surfaces in the context of extracorporeal circulation such as, for example, haemodialysis and ECMO (“extracorporeal membrane oxygenation“), LVAD (“left ventricular assist device“) and similar devices, AV fistulas, vascular and heart valve prostheses.
• the compounds according to the invention are suitable for the treatment and/or prophylaxis of disorders involving microclot formation or fibrin deposits in cerebral blood vessels or asymptomatic, covert strokes, which may lead to dementia disorders such as vascular dementia or Alzheimer's disease.
• the clot may contribute to the disorder both via occlusions and by binding disease-relevant factors.
• the compounds according to the invention are suitable for the treatment and/or prophylaxis of disorders where, in addition to the pro-coagulant component, the pro -inflammatory component also plays an essential role.
• the pro-inflammatory component also plays an essential role.
• Mutual enhancement of coagulation and inflammation in particular can be prevented by the compounds according to the invention, thus decisively lowering the probability of thrombotic complications.
• the compounds according to the invention are suitable for the treatment and/or prophylaxis in the context of atherosclerotic vascular disorders, inflammatory diseases, such as rheumatic disorders of the locomotor system, inflammatory disorders of the lung, such as pulmonary fibroses, inflammatory disorders of the kidney, such as glomerulonephritides, inflammatory disorders of the intestine, such as Crohn's disease or ulcerative colitis, or disorders, which may be present in the context of an underlying diabetic disease, such as diabetic retinopathy or nephropathy.
• inflammatory diseases such as rheumatic disorders of the locomotor system
• inflammatory disorders of the lung such as pulmonary fibroses
• inflammatory disorders of the kidney such as glomerulonephritides
• inflammatory disorders of the intestine such as Crohn's disease or ulcerative colitis
• disorders which may be present in the context of an underlying diabetic disease, such as diabetic retinopathy or nephropathy.
• the compounds according to the invention can be used for inhibiting tumor growth and the formation of metastases, and also for the prophylaxis and/or treatment of thromboembolic complications, such as, for example, venous thromboembolisms, for cancer patients, in particular those undergoing major surgical interventions or chemo- or radiotherapy.
• inventive compounds are also suitable for the prophylaxis and/or treatment of pulmonary hypertension.
• pulmonary hypertension includes pulmonary arterial hypertension, pulmonary hypertension associated with disorders of the left heart, pulmonary hypertension associated with pulmonary disorders and/or hypoxia and pulmonary hypertension owing to chronic thromboembolisms (CTEPH).
• CTEPH chronic thromboembolisms
• Pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IPAH, formerly also referred to as primary pulmonary hypertension), familial pulmonary arterial hypertension (FPAH) and associated pulmonary arterial hypertension (APAH), which is associated with collagenoses, congenital systemic-pulmonary shunt vitia, portal hypertension, HIV infections, the ingestion of certain drugs and medicaments, with other disorders (thyroid disorders, glycogen storage disorders, Morbus Gaucher, hereditary teleangiectasia, haemoglobinopathies, myeloproliferative disorders, splenectomy), with disorders having a significant venous/capillary contribution, such as pulmonary-venoocclusive disorder and pulmonary-capillary haemangiomatosis, and also persisting pulmonary hypertension of neonatants.
• IPH idiopathic pulmonary arterial hypertension
• FPAH familial pulmonary arterial hypertension
• APAH pulmonary arterial hypertension
• Pulmonary hypertension associated with disorders of the left heart includes a diseased left atrium or ventricle and mitral or aorta valve defects.
• Pulmonary hypertension owing to chronic thromboembolisms comprises the thromboembolic occlusion of proximal pulmonary arteries, the thromboembolic occlusion of distal pulmonary arteries and non-thrombotic pulmonary embolisms (tumour, parasites, foreign bodies).
• the present invention further provides for the use of the inventive compounds for production of medicaments for the treatment and/or prophylaxis of pulmonary hypertension associated with sarcoidosis, histiocytosis X and lymphangiomatosis.
• the compounds according to the invention may also be useful for the treatment of lung, liver and kidney fibrosis.
• the compounds according to the invention are also suitable for the primary prophylaxis of thrombotic or thromboembolic disorders and/or thrombo -inflammatory disorders and/or disorders with increased vascular permeability in patients, in which gene mutations lead to enhanced activity of the enzymes or increased levels of the zymogens - and these are established by relevant tests/measurements of the enzyme activity or zymogen concentrations.
• the present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
• the present invention further provides for the use of the compounds according to the invention for production of a medicament for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
• the present invention further provides a method for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound according to the invention.
• the present invention further provides the compounds according to the invention for use in a method for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound according to the invention.
• the present invention further provides medicaments comprising a compound according to the invention and one or more further active compounds.
• the compounds according to the invention can also be used for preventing coagulation ex vivo, for example for the protection of organ transplants against damage caused by formation of clots and for protecting the organ recipient against thromboemboli from the transplanted organ, for preserving blood and plasma products, for cleaning/pretreating catheters and other medical auxiliaries and instruments, for coating synthetic surfaces of medical auxiliaries and instruments used in vivo or ex vivo or for biological samples which may contain factor XIa.
• the present invention furthermore provides a method for preventing the coagulation of blood in vitro, in particular in banked blood or biological samples which may comprise factor XIa, which method is characterized in that an anticoagulatory effective amount of the compound according to the invention is added.
• the present invention further provides medicaments comprising a compound according to the invention and one or more further active compounds, in particular for the treatment and/or prophylaxis of the disorders mentioned above.
• active compounds suitable for combinations include:
• HMG-CoA 3 -hydroxy-3 -methylglutaryl -coenzyme A reductase inhibitors
• lovastatin Mevacor
• simvastatin Zocor
• pravastatin Pravachol
• fluvastatin Lescol
• atorvastatin Lipitor
• coronary therapeutics/vasodilators especially ACE (angiotensin converting enzyme) inhibitors, for example captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril and perindopril, or All (angiotensin II) receptor antagonists, for example embusartan, losartan, valsartan, irbesartan, candesartan, eprosartan and temisartan, or b -adrenoceptor antagonists, for example carvedilol, alprenolol, bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propanolol and timolol, or alpha-ACE
• plasminogen activators thrombolytics/fibrinolytics
• PAI inhibitors plasminogen activator inhibitor
• TAFI inhibitors thrombin-activated fibrinolysis inhibitor
• t-PA tissue plasminogen activator
• streptokinase streptokinase
• reteplase reteplase
• urokinase plasminogen-modulating substances causing increased formation of plasmin
• anticoagulatory substances anticoagulants
• UHF heparin
• LMW low -molecular-weight heparins
• tinzaparin certoparin, pamaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin
• t-PA tissue plasminogen activator
• LMW low -molecular-weight heparins
• DTI direct thrombin inhibitors
• Pradaxa diabigatran
• atecegatran AZD- 0837
• DP-4088 phosphatidylcholine
• SSR-182289A argatroban
• argatroban argatroban
• bivalirudin and tanogitran BIBT-986 and prodrug BIBT-1011
• hirudin thrombin inhibitors
• direct factor Xa inhibitors for example, rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673/RPR-130673), letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), idraparinux and fondaparinux,
• direct factor Xa inhibitors for example, rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673/RPR-130673), letaxaban (TAK-442), razaxaban (DPC-906),
• platelet aggregation inhibitors substances which inhibit the aggregation of platelets
• thrombocyte aggregation inhibitors such as, for example, acetylsalicylic acid (such as, for example, aspirin), P2Y12 antagonists such as, for example, ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor, elinogrel
• PAR-1 antagonists such as, for example, vorapaxar, PAR-4 antagonists, EP3 antagonists such as, for example, DG041;
• platelet adhesion inhibitors such as GPVI and/or GPIb antagonists such as, for example, Revacept or caplacizumab;
• fibrinogen receptor antagonists for example abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban;
• recombinant human activated protein C such as, for example, Xigris or recombinant thrombomudulin
• “Combinations” for the purpose of the invention mean not only dosage forms which contain all the components (so-called fixed combinations) and combination packs which contain the components separate from one another, but also components which are administered simultaneously or sequentially, provided that they are used for prophylaxis and/or treatment of the same disease. It is likewise possible to combine two or more active ingredients with one another, meaning that they are thus each in two-component or multicomponent combinations.
• inventive compounds can act systemically and/or locally.
• they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.
• 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, which control the release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration can be accomplished with avoidance of a resorption step (for example by an intravenous, intraarterial, intracardiac, intraspinal or intralumbar route) or with inclusion of a resorption (for example by an intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal route).
• Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
• Suitable administration forms for the other administration routes are, for example, pharmaceutical forms for inhalation (including 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 (for example patches), milk, pastes, foams, dusting powders, implants or stents.
• pharmaceutical forms for inhalation including powder inhalers, nebulizers
• nasal drops solutions or sprays
• tablets for lingual, sublingual or buccal administration
• films/wafers or capsules films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, cream
• the inventive compounds can be converted to the administration forms mentioned. This can be accomplished in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable excipients.
• excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), colourants (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour correctants.
• carriers for example microcrystalline cellulose, lactose, mannitol
• solvents e.g. liquid polyethylene glycols
• emulsifiers and dispersing or wetting agents for example sodium dodecy
• the present invention further provides medicaments comprising at least one inventive compound, preferably together with one or more inert nontoxic pharmaceutically suitable excipients, and the use thereof 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.
• the amount is about 5 to 500 mg every 24 hours.
• Method 1 Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 C18 1.8 qm, 50 mm c 1.0 mm; eluent A: water + 0.025% formic acid, eluent B: acetonitrile + 0.025% formic acid; gradient: 0.0 min 10% B 1.2 min 95% B 2.0 min 95% B; oven: 50°C; flow rate: 0.40 ml/min; UV detection: 210-400 nm.
• Method 2 Instrument: Thermo Scientific DSQII; GC: Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m c 200 mhi c 0.33 mih; constant helium flow rate: 1.20 ml/min; oven: 60°C; inlet: 220°C; gradient: 60°C, 30°C/min 300°C (maintained for 3.33 min).
• Method 3 Instrument: Waters ACQUITY SQD UPUC system; column: Waters Acquity UPUC HSS T3 C18 1.8 mih, 50 mm c 1.0 mm; eluent A: water + 0.025% formic acid, eluent B: acetonitrile + 0.025% formic acid; gradient: 0.0 min 5% B 6.0 min 95% B 7.5 min 95% B; oven: 50°C; flow rate: 0.35 ml/min; UV detection: 210-400 nm.
• Method 4 Instrument: Thermo Scientific FT-MS; UHPUC: Thermo Scientific UltiMate 3000; column: Waters HSS T3 C18 1.8 mih, 75 mm c 2.1 mm; eluent A: water + 0.01% formic acid; eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B 2.5 min 95% B 3.5 min 95% B; oven: 50°C; flow rate: 0.90 ml/min; UV detection: 210-400 nm.
• Method 5 Instrument: Agilent MS Quad 6150; HPUC: Agilent 1290; column: Waters Acquity UPUC HSS T3 1.8 mih, 50 mm c 2.1 mm; eluent A: water + 0.025% formic acid, eluent B: acetonitrile + 0.025% formic acid; gradient: 0.0 min 10% B 0.3 min 10% B 1.7 min 95% B 3.0 min 95% B; oven: 50°C; flow rate: 1.20 ml/min; UV detection: 205-305 nm.
• Method 6 Instrument: Waters MS SQ detector 2; GC: Agilent A7890; column: Restek RTX-35 MS, 15 m x 200 qm c 0.33 mhi. gas: helium; oven: 60°C; flow rate: 1.20 ml/min; inlet: 240°C; gradient: 30°C/min 300°C.
• Method 7 Instrument: Shimadzu UCMS-2020; column: CORTECS C18 2.7 mhi. 50 mm c 2.1 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid, gradient: 0.0 min 5% B 2.0 min 95% B 3.0 min 95% B; oven: 40°C; flow rate: 1.0 ml/min; UV detection: 210-400 nm.
• Method 8 Instrument: Shimadzu LCMS-2020; column: CORTECS C18 2.7 qm, 2.1 mm c 50 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid, gradient: 0.0 min 5% B 1.2 min 100% B 2.0 min 100% B; oven: 40°C; flow rate: 1.0 ml/min; UV detection: 210- 400 nm.
• Method 9 Instrument: Shimadzu LCMS-2020; column: Kinetex EVO-C18 2.6 mih, 3.0 mm c 50 mm; eluent A: water + 0.2% ammonium hydroxide, eluent B: acetonitrile, gradient: 0.0 min 10% B 2.0 min 95% B 3.0 min 95% B; oven: 45°C; flow rate: 1.2 ml/min; UV detection: 210-400 nm.
• Method 10 Instrument: Shimadzu LCMS-2020; column: CORTECS C18 2.7 mih, 50 mm c 2.1 mm; eluent A: water + 0.09% formic acid, eluent B: acetonitrile + 0.1% formic acid, gradient: 0.0 min 5% B 1.2 min 100% B 2.0 min 100% B; oven: 40°C; flow rate: 1.0 ml/min; UV detection: 210- 400 nm.
• Method 11 Instrument: Shimadzu LC-MS-2020; column: Ascentis Express C18 2.7 pm, 50 mm c 2.1 mm; eluent A: water with 0.05% trifluoroacetic acid, eluent B: acetonitrile with 0.05% trifluoroacetic acid; gradient: 0.0 min 5% B 1.2 min 100% B 1.7 min 100% B 1.75 min 5% B 2.0 min 5% B; oven: 40°C; flow rate: 1.5 ml/min; UV detection: 210-400 nm.
• Method 12 Instrument: Shimadzu LC-MS-2020; column: Ascentis Express C18 2.7 pm, 50 mm c 3.0 mm; eluent A: water with 0.05% trifluoroacetic acid, eluent B: acetonitrile with 0.05% trifluoroacetic acid; gradient: 0.0 min 5% B 1.2 min 95% B 1.7 min 95% B 1.8 min 5% B 2.0 min 5% B; oven: 40°C; flow rate: 1.5 ml/min; UV detection: 210-400 nm.
• Method 13 Instrument: Shimadzu LCMS-2020; column: Kinetex EVO C18 2.6 pm, 50 mm c 3.0 mm; eluent A: water + 0.03% ammonium hydroxide, eluent B: acetonitrile, gradient: 0.0 min 10% B 1.1 min 95% B 2.0 min 95% B; oven: 40°C; flow rate: 1.2 ml/min; UV detection: 210- 400 nm.
• Method 14 Instrument: Shimadzu LCMS-2020; column: Kinetex EVO C18 2.6 pm, 50 mm c 3.0 mm; eluent A: water + 0.03% ammonium hydroxide, eluent B: acetonitrile, gradient: 0.0 min 10% B 2.0 min 95% B 3.0 min 95% B; oven: 40°C; flow rate: 1.2 ml/min; UV detection: 210- 400 nm.
• Method 15 Instrument: Waters Single Quad MS; HPLC: Waters UPLC Acquity; column: Waters BEH C18 1.7 pm, 50 mm c 2.1 mm; eluent A: water + 0.025% ammonia, eluent B: acetonitrile; gradient: 0.0 min 8% B 0.1 min 8% B 1.8 min 95% B 3.5 min 95% B; oven: 50°C; flow rate: 0.45 ml/min; UV detection: 210-400 nm.
• Method 16 Instrument: Waters TOF instrument; UPLC: Waters Acquity I-CLASS; column: Waters HSST3 C18 1.8 pm, 50 mm c 2.1 mm; eluent A: water + 0.01% formic acid; eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 2% B 0.5 min 2% B 7.5 min 95% B 10.0 min 95% B; oven: 50°C; flow rate: 1.00 ml/min; UV detection: 210-400 nm.
• Method 17 Instrument: Waters TOF instrument; UPLC: Waters Acquity I-CLASS; column: Waters Acquity UPLC Peptide BEH C18, 300A, 1.7 pm; 150 mm x 2.1 mm; eluent A: water + 0.01% formic acid, eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 90% A 0.25 min 90% A 8.0 min 45% A 10.0 min 2% A 12.0 min 2% A; oven: 50°C; flow rate: 0.475 ml/min; UV detection: 210 nm.
• Method 18 Instrument: Waters TOF instrument; UPLC: Waters Acquity I-CLASS; column: Waters Acquity UPLC HSS T3, 1.8 pm, 50 mm x 1 mm; eluent A: water + 0.01% formic acid, eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 95% A 6.0 min 5% A 7.5 min 5% A; oven: 50°C; flow rate: 0.35 ml/min; UV detection: 210 nm.
• Method 19 Instrument: Shimadzu LCMS-2020; column: Poroshell HPH C18 2.7 pm, 50 mm x 3.0 mm; eluent A: water 6.5 mM ammonium carbonate, eluent B: acetonitrile, gradient: 0.0 min 10% B 2.1 min 95% B 2.7 min 95% B 2.75 min 10% B; oven: 40°C; flow rate: 1.2 ml/min; UV detection: 190-400 nm.
• Microwave reactor used was a "single-mode" instrument of the EmrysTM Optimizer type.
• the compounds according to the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain a sufficiently basic or acidic functionality.
• a salt can be converted to the corresponding free base or acid by various methods known to the person skilled in the art.
• any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process.
• names and structural formulae such as“hydrochloride”,“trifluoroacetate”, “sodium salt” or "x HQ”, “x CF 3 COOH”, “x Na + " should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.
• the crude product was either purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate mixtures or dichloromethane / methanol mixtures) or preparative HPLC (reversed phase, eluent: water / acetonitrile gradients or water / methanol gradients).
• reaction mixture was heated to 80-100°C and stirred at this temperature overnight, followed by the addition of saturated aqueous sodium bicarbonate solution (5-7 ml/mmol of the respective ether) and tetrakis(triphenylphosphine)palladium(0) (0.03-0.05 eq.). Stirring was then continued at 80-100°C for additional 2-72 h and the reaction mixture was either filtered over silica gel and eluted with dichloromethane or extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered.
• saturated aqueous sodium bicarbonate solution 5-7 ml/mmol of the respective ether
• tetrakis(triphenylphosphine)palladium(0) 0.03-0.05 eq.
• the crude product was either purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate mixtures or dichloromethane / methanol mixtures) or preparative HPLC (reversed phase, eluent: water / acetonitrile gradients or water / methanol gradients).
• the crude product was then purified either by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate mixtures or dichloromethane / methanol mixtures) or preparative HPLC (reversed phase, eluent: water / acetonitrile gradients or water / methanol gradients) or used in the subsequent reaction without further purification.
• column chromatography sica gel, eluent: cyclohexane / ethyl acetate mixtures or dichloromethane / methanol mixtures
• preparative HPLC reversed phase, eluent: water / acetonitrile gradients or water / methanol gradients
• the crude product was purified either by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate mixtures or dichloromethane / methanol mixtures) or preparative HPLC (reversed phase, eluent: water / acetonitrile gradients or water / methanol gradients) or used in the subsequent reaction without further purification.
• the respective pyridinone derivative (1.0 eq.) was dissolved in a 4: 1 mixture of 2-propanol and acetone (0.05-0.15 M) and 1,1,3,3-tetramethylguanidine (3.0-5.0 eq.) was added at RT. After stirring or shaking for 15 min, the respective a-bromo-ester or a-bromo-amide derivative (1.0-2.5 eq.) was added and stirring or shaking was continued overnight at RT.
• the crude mixture was then directly purified by preparative HPLC or concentrated under reduced pressure and the crude mixture was purified by preparative HPLC (reversed phase, eluent: water / acetonitrile gradients or water / methanol gradients).
• reaction mixture was cooled to RT and either directly concentrated under reduced pressure or diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
• the crude product was purified either by column chromatography (cyclohexane / ethyl acetate mixtures or dichloromethane / methanol mixtures) or preparative HPLC (reversed phase, eluent: water / acetonitrile gradients or water / methanol gradients).
• (2R)-2-Bromobutanoic acid (single stereoisomer) (3.5 g, 21.2 mmol, 1.1 eq.), pyridine (1.7 ml, 21.2 mmol, 1.1 eq.) and T3P (17.2 ml, 50% solution in ethyl acetate, 28.9 mmol, 1.5 eq.) were added under argon atmosphere at 0-5°C to a suspension of 4-amino-2-fluorobenzamide (3.0 g, 19.3 mmol) in tetrahydrofuran (30 ml). The reaction mixture was allowed to warm to RT and stirred for 30 min.
• reaction mixture was then cooled to 10°C, mixed dropwise with water (35 ml), stirred for 15 min, followed by the addition of further water (25 ml), and stirred for 30 min.
• the forming precipitate was fdtered, washed with water and dried in vacuo. Yield: 5.23 g (90% of theory). From the combined fdtrates, further precipitate formed which was fdtered, washed with water and dried in vacuo. Yield: 0.5 g (9% of theory).
• Separation method 1 SFC: column: Daicel Chiralpak AD 20 pm, 450 mm x 50 mm; eluent: 75% carbon dioxide / 25% 2-propanol; temperature: 40°C; flow rate: 400 ml/min; UV detection: 210 nm.
• Separation method 2 Single stereoisomer 3 and single stereoisomer 4 eluted as a mixture in the first separation. This mixture was then separated according to the following conditions: SFC: column: Daicel Chiralpak AD 20 pm, 450 mm x 50 mm; eluent: 20% carbon dioxide / 80% 2-propanol; temperature: 40°C; flow rate: 400 ml/min; UV detection: 210 nm.
• Separation method 1 SFC: column: Daicel Chiralpak AD 20 pm, 450 mm x 50 mm; eluent: 75% carbon dioxide / 25% 2-propanol; temperature: 40°C; flow rate: 400 ml/min; UV detection: 210 nm.
• Separation method 2 Single stereoisomer 3 and single stereoisomer 4 eluted as a mixture in the first separation. This mixture was then separated according to the following conditions: SFC: column: Daicel Chiralpak AD 20 pm, 450 mm x 50 mm; eluent: 20% carbon dioxide / 80% 2-propanol; temperature: 40°C; flow rate: 400 ml/min; UV detection: 210 nm.
• (2/Z)-2-methyloxirane (single stereoisomer) (5.00 g, 86.1 mmol, 1.0 eq.) was added and the mixture was stirred at -40°C for 5 h, followed by the addition of saturated aqueous solution of ammonium chloride and ice in aqueous hydrochloric acid (6 N) at -20°C.
• the mixture was extracted with diethyl ether and the combined organic layers were washed with saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
• the residue was purified by column chromatography (silica gel, eluent: «-hexane / ethyl acetate 4: 1). Yield: 8.0 g (90% purity, 48% of theory).
• 1,2-dichloroethane 150 ml was added iodomethane (31 ml, 490 mmol, 10.0 eq.) at 0°C. After stirring at 40°C for 72 h, the reaction mixture was filtered through a pad of Celite ® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: «-hexane / ethyl acetate 8: l to 1: 1). Yield: 1.90 g (20% of theory).
• tert- Butyl acetate (4.00 g, 34.4 mmol, 2.0 eq.) was added dropwise at -78°C to a stirred solution of lithium diisopropylamide (17.2 ml, 34.4 mmol, 2 M in tetrahydrofuran / «-hexane, 2.0 eq.) in tetrahydrofiiran (50 ml). After stirring for 0.5 h, the mixture was warmed to -40°C. Diethylaluminum chloride (34.4 ml, 34.4 mmol, 1 M in «-hexane, 2.0 eq.) was added over a period of 5 min and stirring was continued for further 15 min.
• (2.Y)-2-methyloxirane (single stereoisomer) (1.00 g, 17.2 mmol, 1.0 eq.) was added and the mixture was stirred at -40°C for 5 h, followed by the addition of saturated aqueous solution of ammonium chloride and ice in aqueous hydrochloric acid (6 N) at - 20°C.
• the mixture was extracted with diethyl ether.
• the combined organic layers were washed with saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
• the residue was purified by column chromatography (silica gel, eluent: «-hexane / ethyl acetate 4: 1). Yield: 1.50 g (90% purity, 45% of theory).
• N, N, N', A'-Tetramethylnaphthalene -1,8 -diamine 14.36 g, 66.99 mmol, 1.1 eq., weighed out in glove box! was added under argon atmosphere at 0-4°C to a solution of tert- butyl (4,Y)-4- hydroxypentanoate (single stereoisomer) (13.10 g, 60.90 mmol) in dichloromethane (260 ml).
• reaction mixture was stirred at RT for 30 min, cooled again to 0-4°C, mixed with trimethyloxonium tetrafluoroborate (19.91 g, 127.89 mmol, 2.1 eq., weighed out in glove box!), stirred for 30 min at 0-4°C and then for 60 min while allowing to warm to RT.
• the reaction mixture was quenched with water (250 ml) and diluted with dichloromethane (150 ml). The precipitate was filtered off and discarded. After phase separation, the aqueous phase was extracted two times with dichloromethane.
• Lithium diisopropylamide (5.7 ml, 11.4 mmol, 2.0 M in tetrahydrofuran, 1.5 eq.) was added at -78°C to a solution of tert- butyl (4.Y)-4-mcthoxypcntanoatc (single stereoisomer) (1.50 g, 7.6 mmol, 1.0 eq.) in tetrahydrofuran (60 ml).
• Trifluoroacetic acid (13.3 ml, 172.6 mmol, 20 eq.) was added dropwise under argon atmosphere to an ice-cooled solution of tert- butyl (4.Y)-2-bromo-4-methoxypentanoate (mixture of two diastereomers) (2.7 g, 85% purity, 8.6 mmol) in dichloromethane (50 ml). The reaction mixture was stirred at RT for 2 h, followed by the addition of further trifluoroacetic acid (3.3 ml, 43.2 mmol, 5.0 eq.).
• Lithium hydroxide monohydrate (233 g, 5.55 mol, 2.1 eq.) was added at RT to a solution of methyl (4.Y)-2-bromo-4-methoxypentanoate (mixture of two diastereomers) (625 g, 94% purity, 2.61 mol) in a mixture of tetrahydrofuran / water (3: 1, 6.1 1).
• the reaction mixture was stirred at RT overnight and mixed with 1 N aqueous hydrochloric acid (5 1).
• the aqueous phase was extracted with 2- methyltetrahydrofuran.
• the organic phase was dried and evaporated under reduced pressure.
• the crude material was used without further purification. Yield: 595 g (94% purity, quantitative of theory).
• reaction mixture was stirred at RT for 2 h, quenched with water and diluted with ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: dichloromethane / methanol gradient). Yield: 1.91 g (86% of theory).
• tert- Butyl 4-oxobutanoate 3,3,3-Triacetoxy-3-iodophthalide (123.7 g, 291.6 mmol, 2.0 eq.) was added in portions at 0°C to a mixture of tert- butyl 4-hydroxybutanoate (23.4 g, 145.8 mmol, 1.0 eq.) and sodium bicarbonate (24.5 g, 291.6 mmol, 2.0 eq.) in dichloromethane (500 ml). After stirring at RT for 2 h, the reaction mixture was quenched by the addition of a mixture of saturated aqueous solution of sodium carbonate and sodium thiosulfate (1: 1), stirred for further 30 min and extracted with dichloromethane.
• Iodomethane 34.82 g, 245.3 mmol, 10.0 eq.
• a mixture of tert- butyl 4-cyclopropyl-4-hydroxybutanoate (racemate) (5.78 g, 85% purity, 24.5 mmol) and freshly prepared silver(I) oxide (17.05 g, 73.6 mmol, 3.0 eq.) in 1,2-dichloroethane (100 ml).
• the resulting mixture was filtered through Celite ® . The filtrate was concentrated under reduced pressure.
• Lithium diisopropylamide (4.9 ml, 2.0 M in tetrahydrofuran, 9.9 mmol, 1.5 eq.) was added under argon atmosphere at -78°C to a solution of tert- butyl 4-cyclopropyl-4-methoxybutanoate (racemate) (1.44 g, 6.6 mmol) in tetrahydrofuran (20 ml).
• Trifluoroacetic acid (6.2 ml, 80.2 mmol, 20 eq.) was added dropwise under argon atmosphere to an ice-cooled solution of tert- butyl 2-bromo-4-cyclopropyl-4-methoxybutanoate (mixture of stereoisomers) (1.47 g, 80% purity, 4.01 mmol) in dichloromethane (40 ml).
• the reaction mixture was stirred at RT for 1.5 h, concentrated in vacuo and coevaporated two times with dichloromethane. The residue was purified by column chromatography (silica gel, eluent: dichloromethane / methanol gradient). Yield: 641 mg (67% of theory).
• 2-Bromo-4-cyclopropyl-4-methoxybutanoic acid (mixture of stereoisomers) (641 mg, 2.70 mmol), pyridine (241 pi, 2.97 mmol, 1.1 eq.) and T3P (2.37 ml, 50% solution in ethyl acetate, 4.06 mmol, 1.5 eq.) were added under argon atmosphere at RT to a solution of 4-aminobenzamide (368 mg, 2.70 mmol, 1.0 eq.) in tetrahydrofuran (15 ml).
• reaction mixture was stirred at RT for 1.5 h before additional 4-aminobenzamide (110 mg, 0.81 mmol, 0.3 eq.) and T3P (316 pi, 50% solution in ethyl acetate, 0.54 mmol, 0.2 eq.) were added and stirred for another 1 h.
• the reaction mixture was quenched with water and diluted with ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. Yield: 941 mg.
• tert- Butyl (4R)-4-(difluoromethoxy)pentanoate [Bromo(difluoro)methyl](trimethyl)silane (6.64 g, 32.7 mmol, 3.0 eq.) and potassium hydrogen difluoride (5.11 g, 65.4 mmol, 6.0 eq.) were added at RT to a mixture of tert- butyl (4R)-4- hydroxypentanoate (single stereoisomer) (2.00 g, 10.9 mmol) in dichloromethane (7 ml) and water (7 ml) in a plastic bottle.
• Lithium diisopropylamide (3.9 ml, 2.0 M in tetrahydrofuran, 7.7 mmol, 1.2 eq.) was added at -78°C under argon atmosphere to a solution of tert- butyl (4R)-4-(difluoromethoxy) pentanoate (single stereoisomer) (1.50 g, 6.4 mmol) in tetrahydrofuran (20 ml).
• Lithium diisopropylamide (8.9 ml, 2.0 M in tetrahydrofuran, 17.8 mmol, 1.2 eq.) was added at -78°C to a solution of tert- butyl (4.Y)-4-(difluoromcthoxy)pcntanoatc (single stereoisomer) (3.50 g, 14.8 mmol, 1.0 eq.) in tetrahydrofuran (40 ml).
• Separation method 1 SFC: column: Daicel Chiralpak IE 5 pm, 250 mm x 20 mm; eluent: 80% carbon dioxide / 20% methanol; temperature: 35°C; flow rate: 80 ml/min; UV detection: 210 nm.
• Separation method 2 Single stereoisomer 1 and single stereoisomer 2 eluted as a mixture in the first separation, this mixture was then separated according to the following conditions: SFC: column: Daicel Chiralpak IF 5 pm, 250 mm x 20 mm; eluent: 88% carbon dioxide / 12% methanol; temperature: 35°C; flow rate: 80 ml/min; UV detection: 210 nm.
• Lithium diisopropylamide solution (8.0 ml, 2.0 M in tetrahydrof iran, 16.0 mmol, 1.2 eq.) was added under argon atmosphere at -78°C to a solution of ethyl 5, 5-difluoro-4-methoxypentanoate (racemate) (2.90 g, 90% purity, 13.3 mmol, 1.0 eq.) in tetrahydrofiiran (70 ml).
• Lithium hydroxide 255 mg, 10.6 mmol, 2.0 eq. was added at RT to a solution of ethyl 2-bromo- 5,5-difluoro-4-methoxypentanoate (mixture of stereoisomers) (1.72 g, 85% purity, 5.3 mmol) in a mixture of tetrahydrofuran and water (3: 1, 20 ml).
• the reaction mixture was stirred at RT for 100 min and then acidified with aqueous hydrochloric acid (I N). After removing all volatiles under reduced pressure, the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (at ⁇ 30°C and >100 mbar). The crude product was used without further purification. Yield: 1.65 g.
• 2-Bromo-5,5-difluoro-4-methoxypentanoic acid (mixture of stereoisomers) (1.65 g, 90% assumed purity of crude material, 6.0 mmol), pyridine (0.53 ml, 6.6 mmol, 1.1 eq.) and T3P (5.3 ml, 50% solution in ethyl acetate, 9.0 mmol, 1.5 eq.) were added under argon atmosphere at RT to a mixture of 4-aminobenzamide (817 mg, 6.0 mmol, 1.0 eq.) in tetrahydrofuran (20 ml). The reaction mixture was stirred at RT for 1 h, mixed with water, stirred for additional 15 min and mixed with additional water.
• SFC 1 column: Chiralpak AD-H, 50 mm x 4.6 mm; eluent: 80% carbon dioxide / 20% ethanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.
• SFC 2 column: Chiralpak AD-H, 50 mm x 4.6 mm; eluent: 60% carbon dioxide / 40% ethanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.
• the forming precipitate was fdtered, washed with water and dried in vacuo. Yield: 5.7 g (75% of theory).
• the combined fdtrates were extracted with ethyl acetate.
• the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
• the residue was crystallized from water and the precipitate dried in vacuo. Yield: 1.5 g (20% of theory).
• trimethoxymethane (688 ml, 6.28 mol, 2.5 eq.) followed by sulfuric acid (16.7 ml, 314 mmol, 0.125 eq.) were again added at RT to a solution ofthe crude material in methanol (5.1 1).
• the reaction mixture was stirred at 50°C for 24 h and concentrated under reduced pressure. This procedure was repeated one more time to allow for complete conversion of the reaction.
• the resulting residue was mixed with ethyl acetate and the mixture washed with 0.5 N aqueous sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure.
• the crude material was used without further purification. Yield: 625 g (94% purity, quantitative of theory).
• Propionaldehyde (3.6 ml, 50.1 mmol, 1.1 eq.) was added dropwise at RT to a mixture of 2-bromo-4- chlorobenzaldehyde (10.0 g, 45.6 mmol) and sodium hydroxide (0.18 g, 4.6 mmol, 0.1 eq.) in methanol (100 ml). The mixture was stirred at RT for 1 h, followed by the addition of acetic acid to adjust the pH value to 6. The resulting mixture was stirred further 16 h and then concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate.
• Tris(triphenylphosphine)rhodium(I) chloride (3.2 g, 3.4 mmol, 0.3 eq.) was added at RT under nitrogen atmosphere to a mixture of 3-(2-bromo-4-chlorophenyl)-2-methylprop-2-en-l-ol ( E/Z mixture) (3.0 g, 11.5 mmol, 1.0 eq.) in ethanol (30 ml).
• the resulting mixture was purged with hydrogen gas and stirred at RT for 48 h under hydrogen gas atmosphere (2 bar).
• the reaction mixture was filtered through Celite ® and the filtrate concentrated under reduced pressure.
• the residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate 20: 1). Yield: 1.90 g (59% of theory).
• 2-Bromo-4-chloro-3-fluorobenzoic acid (5.00 g, 19.7 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (150 ml), cooled to 0°C and a solution of borane tetrahydrofuran complex (59 ml, 1.0 M in tetrahydrofuran, 59 mmol, 3.0 eq.) was added dropwise. The mixture was stirred at 0°C for 1 h and at RT for 2 days.
• Racemate 3-(2-Bromo-4-chloro-3-fluorophenyl)-2-methylpropan-l-ol (racemate) 3-(2-Bromo-4-chloro-3-fluorophenyl)-2-methylpropanoic acid (racemate) (2.40 g, 77% purity, 6.25 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (60 ml), cooled to 0°C and a solution of borane tetrahydrofuran complex (19 ml, 1.0 M in tetrahydrofuran, 19 mmol, 3.0 eq.) was added dropwise. The mixture was stirred at 0°C for 1 h and at RT overnight.
• the reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and fdtered.
• the fdtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate 99: 1 to 40:60). Yield: 1.65 g (87% purity, 82% of theory).
• reaction mixture was quenched with a mixture ( 1 : 1) of a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium carbonate and extracted with dichloromethane.
• the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, fdtered and concentrated under reduced pressure.
• the residue was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate 97:3). Yield: 3.90 g (85% purity, 68% of theory).
• the reaction mixture was stirred at RT for 20 h, diluted with aqueous hydrochloric acid (2 N) and stirred at RT for 1 h. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane / ethyl acetate mixtures). Yield: 1.89 g (77% of theory).
• Argon was passed through a mixture of 3,3-dimethyl-l-(trifluoromethyl)-l,2-benziodoxole (3.53 g, 10.7 mmol, 1.0 eq.), (5R)-5-benzyl-2,2,3-trimethyl-4-oxoimidazolidin-l-ium trifluoroacetate (single stereoisomer) (711 mg, 2.14 mmol, 0.2 eq.) and copper(I) chloride (52.9 mg, 535 pmol, 0.05 eq.) for 10 min.
• Argon was passed through a mixture of 3,3-dimethyl-l-(trifluoromethyl)-l,2-benziodoxole (10.6 g, 32.2 mmol, 1.0 eq.), (5 A)-5 -benzyl -2.2.3 -tri methyl -4-oxoimidazolidin- 1 -ium trifluoroacetate (single stereoisomer) (2.14 g, 6.43 mmol, 0.2 eq.) and copper(I) chloride (239 mg, 2.41 mmol, 0.075 eq.) for 10 min.
• Argon was passed through a mixture of 3,3-dimethyl-l-(trifluoromethyl)-l,2-benziodoxole (4.06 g, 12.3 mmol, 1.0 eq.), (5/Z)-5-benzyl-2.2.3-trimethyl-4-oxoimidazolidin-l -ium trifluoroacetate (single stereoisomer) (818 mg, 2.46 mmol, 0.2 eq.) and copper(I) chloride (239 mg, 2.41 mmol, 0.075 eq.) for 10 min.
• reaction mixtures were separately quenched with ice/water (5 1) and the resulting mixtures were combined and extracted three times with dichloromethane (5 1).
• the combined organic layers were washed two times with saturated aqueous ammonium chloride solution (5 1), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure.
• the residue was slurried with petroleum ether (500 ml).
• the precipitated solids were collected by fdtration, washed with petroleum ether (500 ml) and dried in vacuo. Yield: 1070 g (52% of theory).

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