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Definitions

• the invention relates to novel compounds of the formula I having antithrombotic activity which in particular inhibit the protease-activated receptor 1 (PARI), processes for their preparation and their use as medicaments.
• PARI protease-activated receptor 1
• Protease-activated receptor 1 is a thrombin receptor belonging to the class of G protein-coupled receptors (GPCR).
• GPCR G protein-coupled receptors
• the gene for PARI is located on chromosome 5q13, consists of two exons and covers a region of about 27 kb.
• PARI is expressed among others in endothelial cells, smooth muscle cells, fibroblasts, neurons and human platelets. In platelets, PARI is an important receptor of signal transduction involved in the initiation of aggregation of platelets. PARs are activated by proteolytic cleavage of part of the N-terminus of the PARs, revealing a new N-terminal sequence that then activates the receptor (Pharmacol Rev 54: 203-217, 2002).
• Blood clotting is an essential process of blood flow control for mammalian survival.
• the process of coagulation and the subsequent dissolution of the clot after wound healing begins after vascular damage and can be divided into four phases:
• phase of vascular constriction This reduces blood loss into the damaged area.
• the next phase is that of platelet activation by thrombin.
• the platelets aggregate at the site of vascular wall damage and form a still loose platelet clot.
• the protein fibrinogen is mainly responsible for stimulating platelet aggregation. Platelets also bind to exposed collagen of the damaged vessel wall.
• the initially loose platelet aggregate is cross-linked by fibrin. If the thrombus contains only platelets and fibrin, it is a white one Thrombus: If additional red blood cells are present, it is a red thrombus.
• Tissue damage or injury is the result of the extrinsic path. Both approaches involve a greater number of proteins known as coagulation factors.
• the intrinsic pathway requires the coagulation factors VIII 1 IX, X, Xl and XII as well as precalcine, high-molecular kininogen, calcium ions and phospholipids
• Each of these proteins activates Factor X.
• the intrinsic pathway is initiated when precalcine, high molecular weight kininogen binds Factor XI and XII to a negatively charged surface. This moment is called contact phase. Exposure to a vessel wall collagen is the primary stimulus of the contact phase. The result of the contact phase processes is the transformation of prekallekrein into kallekrein, which in turn activates factor XII. Factor XIIa hydrolyses further prekallekrein to kallekrein, so activation is the consequence. With increasing activation of factor XII, factor Xl is activated, leading to the release of bradykinin, a vasodilator. This stops the initial phase of vasoconstriction.
• factor IXIa activates factor IX.
• Factor IX is a proenzyme that contains vitamin K dependent, c-carboxyglutamate (GLA) residues.
• GLA c-carboxyglutamate
• Serine protease activity is involved after binding of Ca 2+ ions to these GLA residues.
• Several of the Serine proteases of the blood coagulation cascade (Factors II, VII, IX and X) contain such vitamin K-dependent GLA residues.
• Factor IXa cleaves the factor X and leads to the activation factor Xa. The prerequisite for the formation of factor IXa is the
• a kinase complex of Ca2 + ions and the factors Villa, IXa and X on the surface of activated platelets.
• One of the reactions of activated platelets is the presentation of phosphatidylserine and phosphatidylinositol along the surfaces. The exposure of these phospholipids makes possible the formation of the kinase complex.
• Factor VIII has the function of a receptor for the factors IXa and X in this process. Factor VIII therefore represents a cofactor in the coagulation cascade.
• factor VIII The activation of factor VIII with the formation of the factor Villa, the actual receptor, requires only a minimal amount of thrombin , As the concentration of thrombin increases, the factor Villa is finally further cleaved and inactivated by thrombin.
• This dual activity of thrombin in relation to factor VIII leads to a self-limiting of the kinase complex formation and thus to a limitation of the blood coagulation.
• Inhibitors of PAR 1 are used, for example, in the European
• Patent applications EP1391451 or EP1391452 US patent applications US 6,063,847 and US 2004/0152736 and international application WO 03/089428.
• the compounds of the formula I according to the invention are suitable for prophylactic as well as for therapeutic use in humans, which suffer from diseases which are associated with thromboses, embolisms, hypercoagulability or fibrotic changes. Examples of such diseases are thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, hypertension, inflammatory diseases, rheumatism, asthma, glomerulonephritis or osteoporosis.
• the compounds of the formula I according to the invention can be used for secondary prevention can be used and are suitable for both acute and long-term therapy.
• the invention therefore relates to a compound of the formula I.
• R 1, R 2, R 3 and R 4 are identical or different and independently of one another denote 1) - (C 1 -C 6) -alkyl, where alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by - (C 6 -C 4) - Aryl, - (C 3 -C 6) -cycloalkyl, Het, halogen, -NH 2, -OH or methoxy,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by - (Cg-C -
• R10 and R15 are the same or different and are independently of each other
• R 16 and R 17 independently of one another denote hydrogen atom or - (C 1 -C 6) -alkyl
• R 5 R 6, R 7, R 8 and R 9 are identical or different and are each independently
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by - (CSS-C ⁇ -aryl, - (C3-C6) - cycloalkyl, Het, halogen , -NH 2, -OH or methoxy,
• R 12 (Co-C 4 ) -alkylene-N (R 12) -C (O) -R 13 where R 12 and R 13 are the same or different and are independently as defined above,
• R5 and R6, R6 and R7, R7 and R8 or R8 and R9 together with the ring atoms to which they are attached form a four- to eight-membered heterocycle which, together with the phenyl ring to which the heterocycle is fused, form a bicyclic system where the heterocyclic part is unsubstituted or monosubstituted, disubstituted or trisubstituted independently of one another by
• the invention further relates to a compound of formula I and / or all stereoisomeric or tautomeric forms of the compound of formula I and / or
• R1, R2, R3 and R4 are the same or different and independently of one another 1) - (Ci-CßJ-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently by - (C3-C6) -cycloalkyl, halogen, -NH2, -OH, methoxy, - (C6-C-
• R 10 and R 15 are identical or different and independently of one another represent 1) hydrogen atom,
• R5, R6, R7, R8 and R9 are the same or different and independently of each other
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, -NH 2 , -OH or methoxy,
• alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by - (C 6 -C 4) -aryl, - (C 3 -C 6) -cycloalkyl, Het, halogen, -NH 2 , -OH or methoxy is substituted, wherein
• Aryl and Het are as defined above
• R5 and R6, R6 and R7, R7 and R8, or R8 and R9 together with the ring atoms to which they are attached form a four- to eight-membered one
• Heterocycle which, together with the phenyl ring to which the heterocycle is fused, forms a bicyclic system selected from the group of benzimidazole, benzisothiazole, benzisoxazole, benzo [1,3] dioxole, benzofuranyl, benzothiazole, benzisoxazole, benzothiofuran, benzothiophene, benzo [ 1, 3] oxathiol, benzoxazole, benzthiazole, benzotriazolyl, quinazoline,
• Cycloalkyl, halogen, -NH2, -OH or methoxy is substituted.
• the invention further relates to a compound of formula I and / or all stereoisomeric or tautomeric forms of the compound of formula I and / or
• R1, R2, R3 and R4 are the same or different and independently of one another
• R10 represents 1) hydrogen atom
• R5, R6, R7, R8 and R9 are the same or different and independently of each other
• R 12 and R 13 are the same and different and independently of one another represent hydrogen atom or - (C 1 -C 4) -alkyl, or
• Ring atoms to which they are attached form a four- to eight-membered heterocycle which, together with the phenyl ring to which the heterocycle is a bicyclic system selected from the group 2,3-dihydro-benzo [1,4] dioxin, benzo [1,3] dioxole, 3,4-dihydro-2H-benzo [1,4] oxazine, 2,3,4,5-tetrahydro-1H-benzo [b] azepine, tetrahydroquinoline, tetrahydroisoquinoline, 1, 2,3,4-tetrahydroquinoxaline or 6,7,8,9-tetrahydro-5-oxa-9 -aza-benzocyclohepten, wherein the heterocyclic part is unsubstituted or monosubstituted or disubstituted by - (C 1 -C 4) -alkyl or halogen.
• Another object of the invention are compounds of formula I from the series
• (C 1 -C 4) -alkyl or "(C 1 -C 6) -alkyl” are meant hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms or 1 to 6 carbon atoms, for example Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, 2,3-dimethylbutyl or neohexyl.
• - (C 1 -C 4) -alkylene denotes hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene, ethylene, 1-methylmethylene, propylene, 1-methylethylene, butylene, 1 Propylmethylene, 1-ethyl-1-methylmethylene, 1, 2 Dimethylethylene, 1, 1-dimethylmethylene, 1-ethylethylene, 1-methylpropylene, 2-methylpropylene.
• - Co-alkylene is a covalent bond.
• Carbon chain is straight-chain or branched and contains 1 to 8 carbon atoms, for example methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy or tertiary-butoxy.
• the term "(C 3 -C 6) -cycloalkyl” is understood to mean radicals such as compounds derived from 3- to 6-membered monocycles, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, by the term "- (C 6 -C 14) -Aryl "are understood as meaning aromatic carbon radicals having 6 to 14 carbon atoms in the ring.
• - (C ⁇ -C ⁇ -Arylreste are for example
• Naphthyl radicals and in particular phenyl radicals are preferred aryl radicals.
• Het is understood as meaning ring systems having 4 to 15 carbon atoms which are present in one, two or three interconnected ring systems and which, depending on the ring size, contain one, two, three or four identical or different heteroatoms from the series oxygen, nitrogen
• these ring systems are the radicals acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H Quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquino
• Phenoxathiinyl phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazolyl, Pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1, 2, 4-thiadia
• R5 and R6, R6 and R7, R7 and R8 or R8 and R9 together with the ring atoms to which they are attached form a four- to eight-membered heterocycle which, together with the phenyl ring to which the heterocycle is fused, form a bicyclic system compounds are understood to consist of two interconnected ring systems in which one ring represents a phenyl radical and the other ring forms a partially saturated or aromatic ring system which, depending on the ring size, contains one, two or three identical or different heteroatoms from the series oxygen, Containing nitrogen or sulfur.
• ring systems are radicals such as benzimidazole, benzisothiazole, benzisoxazole, benzo [1,3] dioxole, benzofuranyl, benzothiazole, benzisoxazole, benzothiofuran, benzothiophene, benzo [1,3] oxathiol, benzoxazole, benzthiazole, benztriazolyl, quinazoline, quinazolone, quinoline , 4H-quinolizine, quinoxaline, chroman, chromene, cinnoline, 2,3-dihydrobenzo [1, 4] dioxin, 2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuran, 3,4-dihydro-2H benzo [1,4] oxazine, 2,3-dihydrobenzooxazole, 2,3-dihydrobenzothiazole, 1,3-dixa
• Alkyl radical derived, for example, from the following radicals -CF3, -CHF 2 , -CH 2 F, -CHF-CF 3 , -CHF-CHF 2 , -CHF-CH 2 F, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CF 2 -CF 3 , -CF 2 -CHF 2 , -CF 2 -CH 2 F, -CH 2 -CHF-CF 3 , -CH 2 -CHF- CHF 2 , -CH 2 -CHF-CH 2 F, -CH 2 -CH 2 -CF 3 , -CH 2 -CH 2 -CHF 2 , -CH 2 -CH 2 -CH 2 F, -CH 2 -CF 2 -CF 3 , -CH 2 -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH 2 -CF 2 -
• halogen is understood to mean fluorine, chlorine, bromine or iodine, preference is given to fluorine, chlorine or bromine, in particular fluorine or chlorine
• Suitable protective groups for amino functions are, for example, the t-butoxycarbonyl, the benzyloxycarbonyl or the phthaloyl group and the trityl or tosyl protecting group.
• Suitable protecting groups for the carboxyl function are, for example, alkyl, aryl or arylalkyl esters. Protecting groups can be introduced and removed by well-known or described techniques (see Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley-Interscience).
• the term protecting group may also include corresponding polymer-bound protecting groups.
• the compounds of the invention can be prepared by well-known methods or by methods described herein.
• the invention further relates to a process for the preparation of the compound of the formula I and / or a stereoisomeric form of the compound of the formula I and / or a physiologically acceptable salt of the compound of the formula I which is characterized in that a) a compound of the formula Il
• radicals R5, R6, R7, R8 and R9 are as defined in formula I and Y is chloride, bromide, mesylate or tosylate with a compound of formula III
• radicals R 1 to R 10 are as defined in formula I with a compound Z-CN, where Z is tosylate or bromide, in the presence of a base to give a compound of the formula I, or c) which according to the processes a) or b) prepared compound of formula I either isolated in free form or released from physiologically incompatible salts or converts in the presence of acidic or basic groups in physiologically acceptable salts, or d) a compound of formula I 1 prepared according to the method a) or b) or a suitable precursor of the formula I, which occurs in enantiomeric or diastereomeric forms due to their chemical structure, by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and cleavage of the chiral auxiliary groups in the pure enantiomers or D separates iastereomers.
• the invention further relates to a process for the preparation of the compound of the formula I according to Scheme 1.
• the educts II and III, wherein III optionally (if appropriate) in the form of a salt, are at RT or slightly elevated temperature of 40 0 C to
• Solvent preferably dimethylformamide (DMF), converted to the compound of formula I.
• the radicals R 1 to R 10 are as defined in formula I, Y corresponds to a good leaving group such as chloride, bromide, mesylate or tosylate, preferably bromide or
• pyridines of type VI are converted into the pyridylmethylamines IV in the presence of a nitrogen nucleophile "N" and, if appropriate, a subsequent reaction to expose the -NH 2 group
• nitrogen nucleophiles come ammonia, which directly without further exposure to the compounds of type IV, azides, such as sodium azide, which must be post-reduced to establish the amino function, including triphenylphosphine (Bioorg.Med.Chem., Lett., 2925, 2002) or noble metal catalysts such as palladium or platinum in the presence of hydrogen (J. Med. Chem. 5005, 2002), phthalimide, which must be subsequently treated with hydrazine to expose the amino function (J. Med. Chem.
• the nitrile function is carried out with reducing agents such as hydrogen in the presence of metal catalysts such as Palladium or Raney nickel reduced to the type IV amines. If the nitrile function is reacted before reduction with organometallic reagents such as Grignard or organolithium compounds, the substituent R10 can also be introduced in this way.
• the imines obtained as intermediates can be reduced to the amines IV by sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
• the radicals R1 to R4 and R10 are as defined above. Met stands for -Li or -MgBr.
• compounds of the formula VII - optionally in the form of their salts (HA) - in a solvent such as water, methanol, ethanol, acetic acid, acetonitrile, toluene or suitable mixtures of these solvents, preferably toluene, in the presence of a base, preferably Hünig base , with a cyan source V, preferably cyanogen bromide cyclized to the desired imidazopyridines.
• a solvent such as water, methanol, ethanol, acetic acid, acetonitrile, toluene or suitable mixtures of these solvents, preferably toluene
• a base preferably Hünig base
• a cyan source V preferably cyanogen bromide cyclized to the desired imidazopyridines.
• compounds of formula VII according to scheme 6 can be obtained by reacting amines of formula IX with pyridyl derivatives of the formula VIII.
• the reaction takes place in solvents such as DMF, THF, acetonitrile or ethanol, preferably THF.
• Suitable bases are Hünig base, lithium hexamethyldisilazane or potassium carbonate, preferably lithium hexamethyldisilazane.
• the radicals are as defined above.
• acetophenone derivatives of the formula Xa either directly, for example, with Br2, N-bromo-succinimide (NBS) or phenyl-trimethyl-tribromide, preferably in
• Eissessig, methanol or methanol / THF mixtures are brominated to compounds of formula IIa or else the corresponding ketals of the compound of formula XIa of the acetophenone derivatives X are brominated with, for example, the above Bromierungsreagenzien, preferably phenyl trimethyl tribromide.
• the ketals are cleaved in the presence of acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, preferably sulfuric acid.
• ketals of the formula XI, XIa and XI ' can be obtained starting from the ketones of the formula X by ketalization reactions known to those skilled in the art.
• the reaction to give the compounds of the formula XI in methanol is preferably carried out using methyl orthoformate in the presence of DL-10-camphorsulfonic acid (Scheme 8).
• the radicals R5 to R9 are as defined above.
• the radical W corresponds to a - (C 1 -C 4) -alkyl group.
• the radical W corresponds to ethylene, propylene or butylene or together with the group -OCO- forms a 1,3-dioxo ring of the ring size 5, 6 or 7.
• Ketals of this type are obtained by reaction with alkylene glycols such as ethylene glycol in the presence of acids such as sulfuric acid or para-toluenesulfonic acid and / or dehydrating agents.
• toluene is used in the presence of catalytic amounts of para-toluenesulfonic acid on a water separator.
• a compound of the formula I prepared according to the Schemes 1 or 4 or a suitable precursor of the formula I which occurs in enantiomeric forms by virtue of its chemical structure, can be obtained by salt formation with enantiomerically pure acids or bases, chromatography on stationary chiral phases or derivatization by means of chiral enantiomerically pure compounds How amino acids, separation of the thus obtained diastereomers and cleavage of the chiral auxiliary groups are separated into the pure enantiomers (method c), or the compound of formula I prepared according to the Schemes 1 or 4 can either isolated in free form or in the presence of acidic or basic groups are converted into physiologically acceptable salts (method d).
• Acidic or basic products of the compound of formula I may be in the form of their salts or in free form.
• pharmacologically acceptable salts for example alkali metal or alkaline earth metal salts or hydrochlorides, sulfates, hemisulfates, methylsulfonates, p-toluenesulfonates, all possible phosphates and salts of the amino acids, natural bases or carboxylic acids such as lactates, citrates, tartrates, acetates, adipinates, fumarates, gluconates , Glutamates, maleinates or pamoates.
• physiologically acceptable salts of compounds capable of salt formation of the formula I is carried out in a manner known per se.
• compounds of the formula I contain acidic functionality, basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or even basic amino acids, such as lysine, ornithine or arginine, stable alkali, alkaline earth or optionally substituted ammonium salts.
• Basic groups of the compounds of the formula I form acid addition salts with acids.
• both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, hemic-sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, A-bromobenzenesulfone, Cyclohexylamidosulfon-, trifluoromethylsulfone, 2
• Hydroxyethanesulfonic acetic, oxalic, tartaric, succinic, glycerol phosphoric, lactic, malic, adipic, citric, fumaric, maleic, gluconic, glucuronic, palmitic or trifluoroacetic acid.
• the compound of formula I if it occurs as a mixture of diastereomers or enantiomers or obtained in the selected synthesis as mixtures thereof, separated into the pure stereoisomers, either by chromatography on an optionally chiral support material, or, if the racemic Compound of formula I is capable of salt formation, a fractional crystallization of diastereomeric salts formed with an optically active base or acid as an excipient can also be carried out.
• Suitable chiral stationary phases for the thin-layer or column chromatographic separation of enantiomers For example, modified silica gel carriers (so-called Pirkle phases) and high molecular weight carbohydrates such as triacetyl cellulose.
• gas chromatographic methods can also be used on chiral stationary phases according to appropriate derivatization known to the person skilled in the art.
• an optically active, usually commercially available base such as (-) - nicotine, (+) - and (-) - phenylethylamine, quinine bases, L-lysine or L- and D-arginine the different soluble formed diastereomeric salts, the less soluble component as a solid isolated, the more readily soluble diastereomer from the mother liquor deposited and recovered from the thus obtained diastereomeric salts, the pure enantiomers.
• racemic compounds of formula I which contain a basic group such as an amino group, with optically active acids such as (+) - camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L- Convert lactic acid and (+) and (-) - mandelic acid into the pure enantiomers.
• optically active acids such as (+) - camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L- Convert lactic acid and (+) and (-) - mandelic acid into the pure enantiomers.
• the chirality of the introduced in enantiomerically pure form amino acid or alcohol residue can be used to separate the isomers by performing a separation of the diastereomers now present by crystallization or chromatography at suitable stationary phases and then splits off the entrained chiral moiety by suitable methods again.
• the invention also relates to pharmaceutical compositions, characterized by an effective content of at least one compound of formula I and / or a physiologically acceptable salt of the compound of formula I and / or an optionally stereoisomeric form of the compound of formula I, together with a pharmaceutically acceptable and physiological compatible carrier, additive and / or other active ingredients and excipients.
• the compounds according to the invention are suitable, for example, for the prophylaxis, secondary prevention and therapy of all diseases which can be treated by inhibition of the protease-activated receptor 1 (PARI).
• PARI protease-activated receptor 1
• the compounds of the invention are suitable both for a prophylactic and for a therapeutic use in humans. They are suitable for both acute treatment and long-term therapy.
• the compounds of formula I can be used in patients suffering from disorders of well-being or diseases associated with thrombosis, embolism, hypercoagulability or fibrotic changes.
• Compounds of formula I are useful in the treatment of patients with disseminated intravascular coagulation, sepsis and other intravascular events associated with inflammation. Furthermore, compounds of the formula I are suitable for the prophylaxis and treatment of patients with atherosclerosis, diabetes and the metabolic syndrome and their consequences. Disorders of the hemostatic system (eg fibrin deposits) have been implicated in mechanisms leading to tumor growth and tumor metastasis, as well as in inflammatory and degenerative joint diseases such as rheumatoid arthritis and osteoarthritis. Compounds of the formula I are suitable for slowing down or preventing such processes.
• fibrotic changes of the lung such as the chronic obstructive pulmonary disease, the adult respiratory distress syndrome (ARDS) and of the eye such as fibrin deposits after eye operations.
• Compounds of formula I are also useful for the prevention and / or treatment of scarring.
• the application of the medicaments according to the invention can be effected by oral, inhalative, rectal or transdermal administration or by subcutaneous, intra-articular, intraperitoneal or intravenous injection.
• the oral application is preferred. It is possible to coat stents with compounds of the formula I and other surfaces which come into contact with blood in the body.
• the invention also relates to a process for the preparation of a medicament which is characterized in that at least one compound of the formula I is brought into a suitable administration form with a pharmaceutically suitable and physiologically tolerable carrier and optionally further suitable active substances, additives or excipients.
• Suitable solid or galenic forms of preparation are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, as well as preparations with protracted release of active ingredient, in whose preparation customary auxiliaries such as carriers, blasting agents, binders, coating substances, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used.
• Commonly used adjuvants are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and theirs
• animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerol, called.
• the pharmaceutical preparations are prepared and administered in dosage units, each unit containing as active ingredient a specific dose of the compound of formula I according to the invention.
• this dose may be up to about 1000 mg, but preferably about 50 to 300 mg and for injection solutions in ampoule form up to about 300 mg, but preferably about 10 to 100 mg.
• Daily dose can be done by single dose in the form of a single dosage unit or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
• Compounds of the formula I can be administered both as monotherapy and in combination or together with all antithrombotics (anticoagulants and platelet aggregation inhibitors), thrombolytic agents (plasminogen activators of any kind), other profibrinolytic substances, antihypertensives, regulators of blood sugar, lipid-lowering agents and antiarrhythmics.
• antithrombotics anticoagulants and platelet aggregation inhibitors
• thrombolytic agents plasma edoxifen, and others
• other profibrinolytic substances antihypertensives, regulators of blood sugar, lipid-lowering agents and antiarrhythmics.
• End products were generally characterized by a chromatographic mass spectroscopic method (LCUV / ESI-MS coupling) and 1 H NMR.
• the compounds are described by specifying the associated retention time in the ionic current (LCMS-rt) and the corresponding M + H + signal in the associated
• Methods performed Method A, standard method if no other is mentioned in the text
• Phenyl (2-pyridyl) methylamine hydrochloride (150 mg) was dissolved in a little water, made alkaline with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 113 mg of the free base were obtained. Of these, 55 mg were dissolved in THF (4 ml), and 2-bromo-1- (3,5-di-tert-butyl-4-hydroxy-phenyl) -ethanone (96 mg, dissolved in 2 ml of THF) was added dropwise with stirring , After stirring at RT for 4 h, it was allowed to stand overnight and then the precipitate formed was filtered off.
• 6-Cyano-nicotinic acid as trifluoroacetate (1 g) was dissolved in methanol (300 ml), treated with Raney nickel (0.224 g) and hydrogenated in a Scierelautoklaven at 80 0 C for 20 h under 10 bar hydrogen pressure. The mixture was then filtered, the residue washed with a water / methanol mixture and the filtrate concentrated. The residue was taken up in ACN / water and freeze-dried. 500 mg of product was obtained which was sufficiently clean for use in the next step.
• 6-Aminomethyl-nicotinic acid trifluoroacetate (390 mg) was dissolved in toluene (35 ml) and treated with Hünig's base (230 ⁇ l). Then, cyanogen bromide (0.35 ml of a 5 M solution in acetonitrile) was slowly added dropwise. After 3 h stirring at RT, the solvent was removed and the residue taken up in water and saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product-containing fractions were combined, freed from acetonitrile and freeze-dried.
• 3-Pentafluorosulfanylbenzoic acid (3.0 g) was dissolved in fuming nitric acid (20 ml) and stirred at RT with exclusion of moisture. Then, concentrated sulfuric acid (1, 5 ml) was added and stirred at 75 0 C. After 6 h of stirring at 75 ° C was allowed to stand overnight, then more sulfuric acid (1, 5 ml) was added and heated to 75 ° C for 8 h. After standing overnight, was added to ice-water and stirred for 2 h. The onset of crystallization was completed overnight in the refrigerator. The precipitate was then filtered off with suction and dried under high vacuum.
• Example 13 2- [2- (3-tert-Butyl-4-methoxy-5-morpholin-4-yl-phenyl) -2-oxo-ethyl] -7-chloro-3-imino-2,3-dihydro- imidazo [1, 5-a] pyridine-6-carboxylic acid methylamide as the trifluoroacetic acid salt
• N-Methoxy-N-methyl-5-pentafluorosulfanyl-3- (2,2,2-trifluoro-acetylamino) -benzamide (20 mg) was dissolved in absolute THF (2 ml) and treated at RT with lithium hexmethyl-di-silazane solution ( 45 ⁇ l, 1 M in THF) for 30 min. At 0 0 C was then stirred
• Methylmagnesium bromide solution (17 .mu.l, 3 M in diethyl ether) was added dropwise. After stirring at RT for 1 h, 1N hydrochloric acid was added dropwise with cooling, followed by water and ethyl acetate. The organic phase was separated and the water phase was extracted twice more with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 17 mg of crude product were obtained.
• the crude product was pre-purified on silica gel (n-heptane / ethyl acetate gradient) and then finally purified by preparative chromatography.
• the product-containing fractions were combined, stripped of acetonitrile and extracted with ethyl acetate three times. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 12 mg of the desired compound were obtained.
• TRAP thrombin receptor activating peptide
• blood was taken from healthy volunteers in 20 ml syringes, in which 2 ml of 3.13% sodium citrate solution was placed. After centrifugation at 150 x g for 20 minutes, the platelet rich plasma (PRP) was separated and treated with 1 ⁇ l PGE1 solution (500 ⁇ g / ml in ethanol) / ml PRP. After incubation at RT for 5 minutes, centrifugation was carried out at 120 ⁇ g for 15 minutes
• the leukocyte-free PRP was transferred to 15 ml portions in 15 ml PP tubes and subtracted at 360xg for 15 minutes to pellet the platelets. Subsequently, the plasma was decanted and the platelet sediment from 5 ml PRP in 1 ml Tyrode (120 mM NaCl, 2.6 mM KCl, 12 mM NaHCO 3 , 0.39 mM NaH 2 PO 4 ⁇ H 2 O, 10 mM HEPES, 0.35% BSA , 5.5 mM glucose, pH 7.4) and adjusted with Tyrode to a platelet count of 3x1 O ⁇ / microliter ( ⁇ L).
• Tyrode 120 mM NaCl, 2.6 mM KCl, 12 mM NaHCO 3 , 0.39 mM NaH 2 PO 4 ⁇ H 2 O, 10 mM HEPES, 0.35% BSA , 5.5 mM glucose, pH 7.4
• the areas under the curves of negative control (Tyrode / DMSO) and positive control (15 ⁇ l agonist / DMSO) were calculated and the difference determined as 100% value.
• the substances to be tested were pipetted in duplicate as dilution series, likewise the AUC of each substance concentration was determined and the% inhibition of the AUC against the control was calculated.
• the IC50 was calculated from the% inhibition using non-linear regression analysis according to the 4-parameter equation.

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