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WO2018184976A1 - Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation - Google Patents

Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation Download PDF

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Publication number
WO2018184976A1
WO2018184976A1 PCT/EP2018/058076 EP2018058076W WO2018184976A1 WO 2018184976 A1 WO2018184976 A1 WO 2018184976A1 EP 2018058076 W EP2018058076 W EP 2018058076W WO 2018184976 A1 WO2018184976 A1 WO 2018184976A1
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hydrogen
substituted
alkyl
group
methyl
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PCT/EP2018/058076
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German (de)
English (en)
Inventor
Alexandros Vakalopoulos
Damian Brockschnieder
Niels Lindner
Ingo Hartung
Frank Wunder
Lisa Dietz
Volkhart Min-Jian Li
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Bayer Pharma Aktiengesellschaft
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Publication of WO2018184976A1 publication Critical patent/WO2018184976A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present application relates to novel substituted imidazo [l, 2-a] pyridinecarboxamides, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases , in particular for the treatment and / or prophylaxis of cardiovascular diseases.
  • cyclic guanosine monophosphate cGMP
  • NO nitric oxide
  • the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP).
  • GTP guanosine triphosphate
  • the previously known members of this family can be divided into two groups according to both structural features and the nature of the ligands: the particulate guanylate cyclases stimulable by natriuretic peptides and the soluble guanylate cyclases stimulable by NO.
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer that is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Also, carbon monoxide (CO) is able to bind to the central iron atom of the heme, with stimulation by CO being significantly less than by NO.
  • CO carbon monoxide
  • guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations.
  • the NO / cGMP system may be suppressed, leading, for example, to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
  • the object of the present invention was to provide novel substances which act as stimulators of soluble guanylate cyclase, and as such are suitable for the treatment and / or prophylaxis of diseases and have the same or improved therapeutic profile compared to the compounds known from the prior art, such as for example, in terms of their in vivo properties, such as their pharmacokinetic and pharmacodynamic behavior, their solubility and / or their metabolism profile and / or their dose-response relationship.
  • the present invention relates to compounds of the general formula (I)
  • A is CH 2 , CD 2 or CH (CH 3 )
  • R 1 is phenyl, wherein phenyl having 1 to 4 substituents independently of one another selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl and (Ci-C i) alkyl may be substituted
  • R 2 is hydrogen, (Ci-C i) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, a group of the formula
  • L 1 is a bond, -C (R U R 12 ) -, oxygen, sulfur or nitrogen,
  • R 7 is hydrogen, (Ci-C i) -alkyl or amino, wherein (Ci-C i) -alkyl may be substituted with 1 to 3 substituents independently selected from the group fluorine, difluoromethyl, trifluoromethyl, hydroxy and amino,
  • R 8 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 7 and R 8 together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle in which the 3- to 5-membered carbocycle may be substituted up to two times by fluorine,
  • R 9 is hydrogen, (C 1 -C 6 ) -alkyl, -NR 13 R 14 , -NO 2 NR 15 R 16 , (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -heterocyclyl, or 6-membered heteroaryl or phenyl, in which (C 1 -C 6) -alkyl having 1 to 3 substituents independently of one another is selected from the group consisting of fluorine, trifluoromethyl, difluoromethoxy, hydroxy, (C 1 -C 4) -alkoxy, (C 3 -C 7) - Cycloalkyl, (C 4 -C 4 ) -heterocyclyl and 5- or 6-membered heteroaryl may be substituted, wherein R is hydrogen, (Ci-C 4 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, wherein (C3 -Cv) -cycl
  • R 11 is hydrogen, (C 1 -C 4 ) -alkyl or amino, in which (C 1 -C 4 ) -alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, hydroxy and amino,
  • R 12 is hydrogen or (Ci-C 4 ) -alkyl, or R u and R 12 together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle, wherein the 3- to 5-membered carbocycle may be substituted up to two times by fluorine, or
  • R 7 and R 11 together with the carbon atoms to which they are attached form a 3- to 5-membered carbocycle, wherein the 3- to 5-membered carbocycle may be substituted up to two times by fluorine, or
  • R 3 is a group of the formula
  • R 10 is 5- or 6-membered heteroaryl or (C 5 -C 4) -heterocyclyl, in which 5- or 6-membered heteroaryl having 1 to 3 substituents independently of one another selected from the group halogen, trifluoromethyl or (Ci-C i) - Alkyl and in which 5-membered heteroaryl may be fused with (C5-Cv) -cycloalkyl, wherein (C5-Cv) -cycloalkyl having 1 or 2 substituents independently selected from the group halogen or (Ci-C i) Alkyl, or
  • R 3 is a group of the formula
  • R 17 is (C 1 -C 8 ) -alkyl, wherein (C 1 -C 8 ) -alkyl may be substituted by phenyl or 5- or 6-membered heteroaryl, wherein phenyl having 1 to 3 substituents independently selected from the group consisting of halogen or (Ci-C i) -alkyl may be substituted, wherein 5- or 6-membered heteroaryl may be substituted with 1 to 3 substituents independently selected from the group halogen or (Ci-C i) -alkyl,
  • R 4 is hydrogen
  • R 5 represents hydrogen, chlorine, fluorine, difluoromethyl, trifluoromethyl or (C 1 -C 4) -alkyl
  • R 6 represents hydrogen or chlorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides Oxides and salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds 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, formic 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 customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atrop isomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of 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 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; due to the comparatively easy manufacturing and detectability are suitable for this purpose, in particular compounds labeled with 3 H or 14 C isotopes.
  • incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • Such modifications of the compounds of the invention may therefore optionally 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 the person skilled in the art, for example by the methods described below and the instructions given in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term "treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • A is CH 2 ,
  • R 1 is phenyl, where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group of fluorine, chlorine or methyl,
  • R 2 is methyl
  • R 3 is a group of the formula
  • L 1 is a bond, -C (R U R 12 ) -, oxygen or sulfur,
  • R 7 is hydrogen, (Ci-C i) -alkyl or amino, wherein (Ci-C i) -alkyl may be substituted with amino, R 8 is hydrogen, or
  • R 9 is hydrogen, (C 1 -C 4 ) -alkyl, -NR 13 R 14 , -NO 2 NR 15 R 16 , (C 3 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -heterocyclyl, or 6-membered heteroaryl or phenyl, in which (C 1 -C 12) -alkyl may be substituted by fluorine, difluoromethyl, trifluoromethyl or methoxy, in which R 13 is hydrogen, methyl, ethyl or (C 3 -C 6 ) -cycloalkyl, wherein (C 3 -C 6) -cycloalkyl may be substituted up to two times by fluorine, in which R is hydrogen or methyl, in which R 15 is hydrogen or methyl, and wherein R 16 is hydrogen or methyl, wherein phenyl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro,
  • R 11 is hydrogen, (Ci-C i) -alkyl or amino, wherein (Ci-C i) -alkyl may be substituted with amino,
  • R 12 is hydrogen, or
  • R 7 and R 11 together with the carbon atoms to which they are attached form a 3- to 5-membered carbocycle
  • R 10 is 5- or 6-membered heteroaryl or (C 5 -C 4) -heterocyclyl, wherein 5- or 6-membered heteroaryl may be substituted with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl or methyl, and wherein 5-membered heteroaryl may be fused with (C5-C6) -cycloalkyl, wherein (C5- C6) cycloalkyl having 1 or 2 substituents independently selected from the group fluorine or methyl, or
  • R 3 is a group of the formula
  • R 17 is (C 1 -C 8 ) -alkyl, in which (C 1 -C 6) -alkyl may be substituted by phenyl, in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine or methyl,
  • R 4 is hydrogen
  • R 5 is hydrogen or methyl
  • R 6 is hydrogen, and the salts, solvates and solvates of the salts of these compounds.
  • A is CH 2
  • R 1 is phenyl, where phenyl may be substituted by 1 or 2 substituents fluorine
  • R 2 is methyl, for a group of the formula
  • L 1 is a bond, -C (R U R 12 ) -, oxygen or sulfur,
  • R 7 is hydrogen, methyl or amino
  • R 8 is hydrogen, or
  • R 9 is hydrogen, (GC 4 ) alkyl, -NR 13 R 14 , -NO 2 NR 15 R 16 , (C 3 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -heterocyclyl, pyrazolyl, pydridyl or Phenyl, wherein (Ci-C i) -alkyl may be substituted with trifluoromethyl, wherein R 13 is hydrogen, methyl, cyclopentyl or cyclohexyl, wherein R 14 is hydrogen or methyl, wherein R 15 is methyl, and wherein R 16 is hydrogen, methyl, in which phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine or chlorine,
  • R 1 1 is hydrogen or amino
  • R 12 is hydrogen, or
  • R 5 is hydrogen or methyl
  • R 6 is hydrogen
  • phenyl may be substituted by 1 or 2 substituents fluorine
  • L 1 is a bond, -C (R 1 'R 12 ) -, oxygen or sulfur,
  • R 7 is hydrogen, methyl or amino
  • R 8 is hydrogen, or
  • R 9 is hydrogen, (C 1 -C 4 ) -alkyl, -NR 13 R 14 , -NO 2 NR 15 R 16 , (C 3 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -heterocyclyl, pyrazolyl, Pyridyl or phenyl wherein (Ci-C i) -alkyl may be substituted with trifluoromethyl, wherein R 13 is hydrogen, methyl, cyclopentyl or cyclohexyl, wherein R 14 is hydrogen or methyl, wherein R 15 is methyl, and wherein R 16 is hydrogen, methyl, in which phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine or chlorine,
  • R 11 is hydrogen or amino
  • R 12 is hydrogen, or
  • R 7 and R u together with the carbon atoms to which they are attached form a 3- to 5-membered carbocycle, and the salts, solvates and solvates of the salts of these compounds.
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention which comprises reacting a compound of the formula (II)
  • R 1 , R 2 , R 4 , R 5 and R 6 each have the meanings given above,
  • T 1 is phenyl or para-nitrophenyl
  • Inert solvents for process steps (II) + (III) - > (I) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons, such as Dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone ( ⁇ ).
  • TBTU is used in conjunction with N-methylmorpholine, HATU in conjunction with N, N-diisopropylethylamine or 1-chloro-N, 2-trimethylprop-1-ene-1-amine.
  • the condensations (II) + (III) -> (I) and is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 60 ° C.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • carboxylic acid of the formula (III) can also first be converted into the corresponding carboxylic acid chloride and this can then be reacted directly or in a separate reaction with an amine of the formula (II) to give the compounds according to the invention.
  • the formation of carboxylic acid chlorides from carboxylic acids is carried out by the methods known in the art, for example by treatment with thionyl chloride, sulfuryl chloride or oxalyl chloride in the presence of a suitable base, for example in the presence of pyridine, and optionally with the addition of dimethylformamide, optionally in a suitable inert solvent.
  • Inert solvents for process steps (V) + (VI) - > ⁇ (I) are, for example, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, acetonitrile, DMF, NMP, DMSO and mixtures thereof. Preference is given to using tetrahydrofuran.
  • Suitable bases for process step (V) + (VI) -> (I) are pyridine, DMAP, trialkylamines, eg triethylamine, N-methylmorpholine, N-methylpiperidine or N, N-diisopropylethylamine and DBU.
  • pyridine is used.
  • the reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 20 ° C to + 120 ° C in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
  • X 1 is a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (IX)
  • R 1 , R 2 , R 4 , R 5 and R 6 each have the meanings given above, and then reacting them in an inert solvent in the presence of zinc and acetic acid, and then optionally cleaving off any protecting groups present, or
  • Inert solvents for process step (VII) + (VIII) - > (IX) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, Toluene, xylene, hexane, cyclohexane or petroleum fractions, alcohols such as methanol, ethanol, tert-butanol, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylpropyleneurea (DMPU), N-methylpyr
  • Suitable bases for process step (VII) + (VIII) -> (IX) are the customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, optionally with the addition of an alkali iodide such as sodium iodide or potassium iodide, alkali alcoholates such as sodium or potassium, Sodium or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N Methyl piperidine, N, N-diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0
  • the reaction is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably at + 20 ° C to + 80 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
  • Inert solvents for ring closure (IX) + (X) -> (XI) are the common organic solvents. These include preferably alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. Preferably, ethanol is used.
  • the ring closure is generally carried out in a temperature range from + 50 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C, optionally in a microwave.
  • the ring closure (IX) + (X) -> (XI) is optionally carried out in the presence of water-withdrawing reaction additives, for example in the presence of molecular sieve (4 ⁇ pore size) or by means of water.
  • the reaction (IX) + (X) -> (XI) is carried out using an excess of the reagent of formula (X), for example with 1 to 10 equivalents of the reagent (X), optionally with the addition of bases (such as sodium bicarbonate) the addition of this reagent can be done once or in several portions.
  • Inert solvents for process step (XI) + 3-methylbutylnitrile-> (XII) are, for example, dioxane, THF, DMF or NMP. It is likewise possible to use mixtures of the solvents mentioned. Preferably, dioxane is used.
  • the reaction is generally carried out in a temperature range from 25 ° C to + 150 ° C, preferably at + 60 ° C to + 120 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
  • Inert solvents for process step (XII) + zinc + acetic » ⁇ (II) are, for example, water, methanol or ethanol. It is likewise possible to use mixtures of the solvents mentioned. Preferably, water is used.
  • the reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 0 ° C to + 80 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
  • Inert solvents for process step (XIII) + diphenylphosphorazidate-> (XIV) are, for example, benzene, xylene, toluene or chlorobenzene. It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used.
  • the reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 25 ° C to + 120 ° C, optionally in a microwave.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • Inert solvents for process step (XIV) - > ⁇ (II) are, for example, diethyl ether, dioxane, THF, methanol, ethanol or water. It is likewise possible to use mixtures of the solvents mentioned.
  • methanol is used
  • the reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 0 ° C to + 60 ° C, optionally in a microwave.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular the compounds listed under R 3 , starting from the compounds of formula (I) obtained by the above method.
  • transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protection groups.
  • reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protection groups.
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention open up a further treatment alternative and thus represent an enrichment of pharmacy.
  • the compounds of the invention act as potent stimulators of soluble guanylate cyclase, have valuable pharmacological properties, and have an improved therapeutic profile, such as in their in vivo properties and / or their pharmacokinetic behavior and / or metabolic profile. It is therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated via direct stimulation of soluble guanylate cyclase and intracellular cGMP increase.
  • the compound of the invention enhances the action of cGMP level enhancing substances such as endothelium-derived relaxing factor (EDRF), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.
  • the compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial arrhythmias and ventricular dysfunction such as atrio-ventricular blockades grade I-III (Till-Till), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles, AV -junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute Coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomy
  • cardiac failure includes both acute and chronic manifestations of cardiac insufficiency, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects.
  • heart failure heart valve defects mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic regurgitation, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve, combined heart valve defects, heart muscle inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcohol-toxic cardiomyopathy, cardiac storage diseases, diastolic cardiac insufficiency and systolic Heart failure and acute phases of Worsening of an existing chronic heart failure.
  • myocarditis myocarditis
  • chronic myocarditis chronic myocarditis
  • acute myocarditis viral myocarditis
  • diabetic cardiac insufficiency diabetic cardiac insufficiency
  • alcohol-toxic cardiomyopathy cardiac storage diseases
  • the compound according to the invention can also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias,
  • Hypertriglyceridemias hyperlipidemias, hypercholesterolemias, abetelipoproteinemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity, obesity and combined hyperlipidaemias and the metabolic syndrome.
  • the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic Ulcers on the extremities, gangrene, CREST syndrome, erythematosis, onychomycosis, rheumatic diseases and to promote wound healing.
  • the compounds according to the invention are suitable for the treatment of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorder
  • LUTS lower urinary tract syndromes
  • FUS lower urinary tract syndromes
  • UI incontinence
  • MUI mixed, urge, stress, or overflow incontinence
  • UUI UUI
  • SUI S
  • kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
  • renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertens
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.
  • the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory syndrome (ARDS), the acute Lung damage (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced emphysema) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory syndrome
  • ALI acute Lung damage
  • AATD alpha-1-antitrypsin deficiency
  • CF cystic
  • the compounds described in the present invention are also agents for controlling central nervous system diseases characterized by disorders of the NO / cGMP system.
  • they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorder, difficulty concentrating in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies Dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis.
  • cognitive disorders such as occur in situations
  • the compounds according to the invention are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous system-related sexual dysiunctions and sleep disorders and for the regulation of pathological disorders of food, consumption and addiction absorption.
  • the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus.
  • the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases as well as inflammatory eye diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic inflammatory bowel disease
  • UC chronic inflammatory bowel disease
  • pancreatitis inflammatory skin diseases as well as inflammatory eye diseases.
  • the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.
  • the compounds according to the invention are for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic Illnesses of the eye, suitable.
  • fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
  • the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.
  • the compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention further relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders, atherosclerosis, dementia disorders and erectile dysfunction.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disease, renal insufficiency, thromboembolic diseases, fibrotic diseases, arteriosclerosis, dementia and erectile dysfunction.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Anti-hypertensives by way of example and by way of example and by way of preference from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-
  • Receptor blockers beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors and diuretics; and or
  • Lipid metabolism-modifying agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP
  • Inhibitors PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor such as, for example and preferably, rivaroxaban (BAY 59-7939), edoxaban (DU-176b), apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • a vitamin K antagonist such as by way of example and preferably coumarin.
  • the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds according to the invention are used in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, embursartan, irbesartan, olmesartan, eprosartan or azilsartan or a dual angiotensin AII antagonist / NEP Inhibitor, such as and preferably LCZ696 (valsartan / sacubitril).
  • an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, embursartan, irbesartan, olmesartan, eprosartan or azilsartan
  • a dual angiotensin AII antagonist / NEP Inhibitor such as and preferably LCZ696 (valsartan / sacubitril).
  • the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan, avosentan, macitentan, atrasentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan, avosentan, macitentan, atrasentan or sitaxsentan.
  • the compounds according to the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as, by way of example and by way of preference, spironolactone, finerenone or eplerenone.
  • a mineralocorticoid receptor antagonist such as, by way of example and by way of preference, spironolactone, finerenone or eplerenone.
  • the compounds of the invention are used in combination with a loop diuretic, such as furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics such as amiloride and triamterene, with aldosterone antagonists, such as spironolactone, potassium canrenoate and eplerenone, and thiazide diuretics, such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.
  • a loop diuretic such as furosemide, torasemide, bumetanide and piretanide
  • potassium-sparing diuretics such as amiloride and triamterene
  • aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone
  • thiazide diuretics such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoproteins antagonists understood.
  • cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors MTP inhibitors
  • MTP inhibitors PPAR-alpha, PPAR gamma and / or PPAR delta agonists
  • cholesterol absorption inhibitors polymeric bile acid adsorbers
  • bile acid reabsorption inhibitors bile acid reabsorption inhibitors
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), anacetrapib, JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as by way of example and preferably torcetrapib (CP-529 414), anacetrapib, JJT-705 or CETP vaccine (Avant).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist, such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as by way of example and preferably pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • a PPAR-delta agonist such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 AK-105
  • SC-435 SC-635.
  • the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, rapidly disintegrating in the oral cavity Pellets, powders, emulsions, suspensions, aerosols or solutions.
  • parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions
  • Ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • These adjuvants include, among others. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers ( For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodec
  • the dosage is about 0.001 to 2 mg / kg, preferably about 0.001 to 1 mg / kg of body weight.
  • Instrament Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A Furnace: 50 ° C; Flow: 0.40 ml / min; UV detection: 210 - 400 nm.
  • Instrument MS Waters
  • instrument HPLC Waters (column Waters X-Bridge C18, 18 mm x 50 mm, 5 ⁇ , eluent A: water + 0.05% triethylamine, eluent B: acetonitrile (ULC) + 0.05% triethylamine, with gradient; Flow: 40 ml / min; UV detection: DAD: 210-400 nm). respectively.:
  • Instrument MS Waters
  • Instrument HPLC Waters (column Phenomenex Luna 5 ⁇ C18 (2) 100A, AXIA Tech 50 x 21.2 mm, eluent A: water + 0.05% formic acid, eluent B: acetonitrile (ULC) + 0.05% formic acid, with Gradient: flow: 40 ml / min; UV detection: DAD: 210-400 nm).
  • Method 11 Instrament: Waters ZQ 2000; Electrospray ionization; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; 25% A, 75% B; Flow: 0.25 ml / min.
  • Instrument Thermo Fisher-Scientific DSQ; chemical ionization; Reactant gas ammonia; Source temperature: 200 ° C; Ionization energy 70eV.
  • Method 13 Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 series; Column: YMC-Triart C18 3 ⁇ 50 x 3 mm; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 100% A -> 2.75 min 5% A -> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.25 ml / min; UV detection: 210 nm.
  • Method 14 GC-MS:
  • Method 16 (LC-MS Analytical): Instrument MS: Waters (Micromass) Quattro Micro; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7 ⁇ 50 x 2.1 mm; Eluent A: 1 l of water + 0.01 mol of ammonium formate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 95% A -> 0.1 min 95% A -> 2.0 min 15% A -> 2.5 min 15% A ⁇ 2.51 min 10% A -> 3.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 210 nm. Method 17 (LC-MS):
  • Device Type MS Waters ZQ
  • Device Type HPLC Agilent 1100 Series
  • UV DAD Column: Thermo Hypersil GOLD 3 ⁇ 20 mm x 4 mm
  • Eluent A 1 l of water + 0.5 ml of 50% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • UV detection 210 nm.
  • the compounds of the invention may be in salt form, for example as trifluoroacetate, formate or ammonium salt, if the Compounds of the invention contain sufficiently basic or acidic functionalities.
  • a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
  • the trifluoroacetate, formate or ammonium salts can be converted into the salt-free form by shaking out an organic solution or suspension with saturated, aqueous sodium bicarbonate solution.
  • amidines may be present as free compounds or proportionally (depending on the preparation in the presence of acetic acid) as acetate salts or acetate solvates.
  • the secondary amides according to the invention can be present as rotational isomers / isomer mixtures, in particular in NMR investigations.
  • Purity specifications generally refer to corresponding peak integrations in the LC / MS chromatogram, but may additionally have been determined with the aid of the 'H-NMR spectrum. If no purity is specified, it is usually a 100% purity according to automatic peak integration in the LC / MS chromatogram, or purity was not explicitly determined.
  • multiplicities of proton signals in 'H-NMR spectra given in the following paragraphs represent the respective observed signal shape and do not take into account higher-order signal phenomena.
  • the indication of the chemical shift refers to the center of the relevant signal.
  • an interval is specified.
  • Solvent or water concealed signals were either tentatively assigned or are not listed. Strongly broadened signals - e.g. caused by rapid rotation of moieties or due to exchanging protons - have also been tentatively assigned (often referred to as broad multiplet or broad singlet) or are not listed.
  • reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 45 mg of the target compound (42% of theory) were obtained.
  • reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, eluent: Acetonitrile / water gradient with the addition of 0.1% TFA). 142 mg of the target compound (63% of theory, purity 99%) were obtained.
  • reaction mixture was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 84 mg of the target compound (71% of theory, purity 98%) were obtained.
  • the clean product fractions were combined and concentrated. 110 mg of the target compound (50% of theory, purity 100%) were obtained. The less clean product fractions were also combined, concentrated and purified again by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1%) TFA). A further 36 mg (15% of theory, purity 91%) of the target compound were obtained.
  • the product fractions were combined, concentrated and the residue was purified again by preparative HPLC (column XBridge C18, 5 ⁇ , 75 x 30 mm, eluent: Milli-Q water, acetonitrile, 1% TFA in water).
  • the product fractions were combined and concentrated.
  • the residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution.
  • the combined aqueous phases were reextracted twice with dichloromethane.
  • the combined organic phases were dried over sodium sulfate, filtered and concentrated. 7 mg of the target compound (10% of theory, purity 97%) were obtained.
  • the product fraction was stirred with dichloromethane / 2N ammonia in methanol, the solution mixed with a little dry ice and concentrated. 9.7 mg (38% of theory, purity 94%) of the target compound were obtained.
  • the reaction mixture was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with the addition of 0.1% TFA).
  • the product fractions were concentrated, the residue dissolved in ethyl acetate, washed once with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution.
  • the organic phase was dried over sodium sulfate, filtered, concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1%) TFA).
  • the product fractions were concentrated, the residue dissolved in ethyl acetate, washed once with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution.
  • the organic phase was dried over sodium sulfate, filtered and concentrated. 20 mg (46% of theory) of the target compound were obtained.
  • the aqueous phase was extracted twice with ethyl acetate.
  • the combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated.
  • the product fractions were combined, concentrated, dissolved in ethyl acetate and washed three times with saturated aqueous sodium bicarbonate solution. Then washed once more with saturated aqueous sodium chloride solution.
  • the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated and dried under high vacuum. There were obtained 106 mg (35% of theory) of the target compound.
  • Soluble guanylyl cyclase converts GTP to cGMP and pyrophosphate (PPi) upon stimulation.
  • PPi is detected by the method described in WO 2008/061626.
  • the signal generated in the test increases as the reaction progresses and serves as a measure of the sGC enzyme activity.
  • the enzyme can be characterized in a known manner, e.g. in terms of turnover rate, stimulability or Michaelis constant.
  • 29 ⁇ M enzyme solution (0-10 nM soluble guanylyl cyclase (prepared according to Hönicka et al., Journal of Molecular Medicine 77 (1999) 14-23) was dissolved in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V ), 0.005% Brij 35, pH 7.5) in the microplate and 1 ⁇ of the stimulator solution (0-10 ⁇ 3-Morpholinosydnonimine, SIN-1, Merck in DMSO) added. It was incubated at RT for 10 min.
  • the enzyme reaction was started by addition of 20 .mu. ⁇ substrate solution (1.25 mM guanosine 5'-triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1%> BSA (fraction V), 0.005%) Brij 35, pH 7.5) and measured continuously luminometrically.
  • substrate solution (1.25 mM guanosine 5'-triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1%> BSA (fraction V), 0.005%) Brij 35, pH 7.5
  • B-2 Effect on recombinant guanylate cyclase reporter cell line
  • MEC minimum effective concentration
  • aorta Rabbits are stunned and bled by a stroke of the neck.
  • the aorta is harvested, detached from adherent tissue, divided into 1.5 mm wide rings and placed individually under bias in 5 ml organ baths with 37 ° C warm, carbogen-fumed Krebs-Henseleit solution of the following composition (in each case mM): Sodium chloride: 119; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1.2; Sodium hydrogencarbonate: 25; Glucose: 10.
  • the force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on a chart recorder.
  • a / D converter DAS-1802 HC, Keithley Instruments Munich
  • phenylephrine is added cumulatively to the bath in increasing concentration.
  • the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC 5 o value).
  • the standard application volume is 5 ⁇ , the DMSO content in the bath solution corresponds to 0.1%>.
  • a commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.
  • the system consists of 3 main components:
  • Implantable transmitters Physiotel® telemetry transmitters
  • Receivers Physiotel® receivers
  • a data acquisition computer through a multiplexer (DSI Data Exchange Matrix).
  • the telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat. animal material
  • the experimental animals are kept individually in macroion cages type 3 after transmitter implantation. You have free access to standard food and water.
  • the TAI 1 PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial.
  • the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
  • the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side.
  • the system's fluid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD TM, 3M).
  • the transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.
  • an antibiotic is administered for infection prophylaxis (Tardomyocel COMP Bayer lml / kg s.c.)
  • the test substances are dissolved in suitable solvent mixtures or suspended in 0.5% Tylose.
  • a solvent-treated group of animals is used as a control.
  • Experimental procedure The existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).
  • the instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).
  • the implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run.
  • the emitted signals can be recorded online by a data acquisition system (Dataquest TM A.R.T. for Windows, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.
  • SBP Systolic blood pressure
  • DBP Diastolic blood pressure
  • MAP Heart rate
  • HR Heart rate
  • ACT Activity
  • test substances will take place on the day of the experiment at 9.00. Following the application, the parameters described above are measured for 24 hours.
  • the collected individual data are sorted with the analysis software (DATAQUEST TM ART TM ANALYSIS). Blank values are assumed 2 hours before application, so that the selected record covers the period from 7:00 am on the trial day to 9:00 am the following day.
  • the data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk.
  • the presorted and compressed measured values are transferred to Excel templates and displayed in tabular form.
  • the filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.
  • the pharmacokinetic parameters of the compounds of the invention are determined in male CD-1 mice, male Wistar rats and female beagle dogs.
  • Intravenous administration is in mice and rats using a species-specific plasma / DMSO formulation and in dogs using a water / PEG400 / ethanol formulation.
  • Oral administration of the solute by gavage is performed in all species based on a water / PEG400 / ethanol formulation. Rats are placed in the right external jugular vein for ease of blood sampling prior to drug administration. The operation is carried out at least one day before the experiment under isoflurane anesthesia and with the administration of an analgesic (atropine / rimadyl (3/1) 0.1 mL s.c.).
  • an analgesic atropine / rimadyl (3/1) 0.1 mL s.c.
  • the blood collection (usually more than 10 times) takes place in a time window, which includes terminal times of at least 24 to a maximum of 72 hours after substance administration.
  • the blood is transferred to heparinized tubes at collection. So then the blood plasma is recovered by centrifugation and optionally stored at -20 ° C until further processing.
  • the pharmacokinetic parameters such as AUC, Cmax, ti 2 (terminal half-life), F (bioavailability), MRI (Mean Residence Time) and CL (clearance) are calculated from the plasma concentration-time profiles determined by means of a validated pharmacokinetic calculation program.
  • the blood / plasma distribution of the substance must be determined in order to adjust the pharmacokinetic parameters accordingly.
  • a defined amount of substance is incubated in heparinized whole blood of the corresponding species for 20 min in a tumble roll mixer. After centrifugation at 1000 g, the concentration in the plasma is measured (by means of LC-MS / MS, see above ) and determined by quotient formation of the CBiut / Cpi aS ma value.
  • CYP cytochrome P450
  • the compounds of the invention were incubated at a concentration of about 0.1 -10 ⁇ .
  • stock solutions of the compounds according to the invention with a concentration of 0.01-1 mM in acetonitrile were prepared, and then pipetted with a 1: 100 dilution into the incubation mixture.
  • the liver microsomes and recombinant enzymes were incubated in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP + , 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase at 37 ° C.
  • Primary hepatocytes were also incubated in suspension in Williams E medium also at 37 ° C.
  • the incubation mixtures were stopped with acetonitrile (final concentration about 30%) and the protein was centrifuged off at about 15,000 ⁇ g. The samples thus stopped were either analyzed directly or stored at -20 ° C until analysis.
  • the analysis is carried out by means of high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS).
  • HPLC-UV-MS / MS ultraviolet and mass spectrometric detection
  • the supernatants of the incubation samples are chromatographed with suitable C18-reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid.
  • the UV chromatograms in combination with mass spectrometry data are used for identification, Structure clarification and quantitative estimation of the metabolites, and the quantitative metabolic decrease of the compound according to the invention in the incubation mixtures.
  • the permeability of a test substance was determined using the Caco-2 cell line, an established in vitro model for permeability predictions at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991) Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells, Biochem., Biophys. 175 (3), 880-885).
  • the Caco-2 cells (ACC No. 169, DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany) were seeded in 24-well plates and cultured for 14 to 16 days.
  • test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks Buffered Salt Solution, Gibco / Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES).
  • transport buffer Hanks Buffered Salt Solution, Gibco / Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES.
  • P app AB the solution containing the test substance was added to the apical side of the Caco-2 cell monolayer and transport buffer to the basolateral side.
  • P app BA the solution containing the test substance was added to the basolateral side of the Caco-2 cell monolayer and transport buffer to the apical side.
  • hERG human ether-a-go-go related gene
  • the functional hERG assay used here is based on a recombinant HEK293 cell line stably expressing the KCNH2 (HERG) gene (Zhou et al., 1998). These cells are assayed by the whole-cell voltage-clamp technique (Hamill et al., 1981) in an automated system (Patchliner TM, Nanion, Kunststoff, D) which controls membrane voltage and hERG potassium current at room temperature measures.
  • the PatchControlHT TM software (Nanion) controls patchliner system, data acquisition and data analysis. The voltage is controlled by 2 EPC-10 quadro amplifiers under the control of the PatchMasterPro TM software (both: HEKA Elektronik, Lambrecht, D).
  • NPC-16 medium resistance chips ( ⁇ 2 ⁇ , Nanion) serve as a planar substrate for the voltage-clamp experiments.
  • NPC-16 chips are filled with intra- and extracellular solution (see Himmel, 2007) as well as with cell suspension.
  • the cell membrane is clamped to the holding potential -80 mV.
  • the following voltage clamping protocol changes the command voltage to +20 mV (duration 1000 ms), -120 mV (duration 500 ms), and back to the holding potential -80 mV; this is repeated every 12 seconds.
  • the test substance solution is pipetted in ascending concentrations (for example 0.1, 1 and 10 ⁇ / L) (exposure for about 5-6 minutes per concentration), followed by several wash-out steps.
  • the amplitude of the inward tail current generated by a potential change from +20 mV to -120 mV serves to quantify the hERG potassium current and is represented as a function of time (IgorPro TM software).
  • the current amplitude at the end of different time periods e.g., test substance stabilization phase, first / second / third test substance concentration
  • concentration-response curve from which the half-maximal inhibitory concentration IC50 of the test substance is calculated.

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Abstract

La présente invention concerne de nouveaux imidazo[1,2-a]pyridine-carboxamides substitués, leurs procédés de production, leur utilisation seuls ou en association pour le traitement et/ou la prévention de maladies ainsi que leur utilisation pour la production de médicaments destinés au traitement et/ou à la prévention de maladies, notamment au traitement et/ou à la prévention de maladies cardiovasculaires.
PCT/EP2018/058076 2017-04-05 2018-03-29 Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation WO2018184976A1 (fr)

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