WO2017121693A1 - Thiazolamides et thiadiazolamides substitués et leur utilisation - Google Patents

Thiazolamides et thiadiazolamides substitués et leur utilisation Download PDF

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WO2017121693A1
WO2017121693A1 PCT/EP2017/050311 EP2017050311W WO2017121693A1 WO 2017121693 A1 WO2017121693 A1 WO 2017121693A1 EP 2017050311 W EP2017050311 W EP 2017050311W WO 2017121693 A1 WO2017121693 A1 WO 2017121693A1
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alkyl
substituted
phenyl
hydrogen
group
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PCT/EP2017/050311
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German (de)
English (en)
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Markus Follmann
Johannes-Peter Stasch
Niels Lindner
Gorden Redlich
Nils Griebenow
Frank Wunder
Volkhart Min-Jian Li
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • 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

Definitions

  • the present application relates to novel substituted thiazole and thiadiazolamides, 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 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, which may, for example, lead to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
  • a NO-independent treatment option for such diseases which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.
  • WO 00/06568 and WO 00/06569 disclose fused pyrazole derivatives and WO 03/095451 discloses carbamate-substituted 3-pyrimidinyl-pyrazolopyridines. 3-Pyrimidinyl-pyrazolopyridines with phenylamide substituents are described in E.M. Becker et al, BMC Pharmacology, 2001, 1 (13).
  • WO 2004/009590 describes pyrazolopyridines with substituted 4-aminopyrimidines for the treatment of CNS diseases.
  • WO 2010/065275 and WO 2011/149921 disclose substituted pyrrolo and dihydropyridopyrimidines as sGC activators.
  • the sGC stimulators described in WO 2012/004259 are fused aminopyrimidines and in WO 2012/004258, WO 2012/143510 and WO 2012/152629 fused pyrimidines and triazines.
  • WO 2012/28647 discloses pyrazolopyridines with various azaheterocycles for the treatment of cardiovascular diseases.
  • WO 2008/052898 describes indazoles with thiazolamide substituents for the treatment of diabetes and related diseases.
  • WO 2006/015263 discloses N-benzyl-indazoles having various amide substituents for the treatment of cancer and benign prostatic hyperplasia.
  • the object of the present invention was to provide novel substances which act as stimulators of soluble guanylate cyclase.
  • the present invention relates to compounds of the general formula (I)
  • V is CR 3 or N
  • R is hydrogen, trifluoromethyl, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, (C 1 -C 4 ) -alkoxycarbonyl, phenyl, pyridyl, -NR 5 R 6 , -S (O) n R 7 , -S0 2 NR 8 R 9 or -OR 10 , wherein (Ci-C6) alkyl having 1 to 3 substituents independently selected from the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy, (Ci-C i) - Alkoxy, hydroxycarbonyl, (C 1 -C 4) -alkoxycarbonyl, (C 1 -C 4) -alkoxycarbonylamino, mono (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamino, phenyl, phenoxy, 4 to
  • R 5 is hydrogen or (Ci-C 6 ) alkyl, wherein (Ci-C6) alkyl in turn with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy and (Ci-C4) alkoxy may be substituted
  • R 6 is hydrogen, (Ci-C 6 ) alkyl, (C 3 -C 7 ) -cycloalkyl, phenyl or 4- to 7-membered heterocyclyl, wherein phenyl in turn having 1 or 2 substituents independently selected from the group halogen , (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy and (C 1 -C 4) -alkylcarbonylamino, or
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle in which 4- to 7-membered heterocycle may be substituted by (C 1 -C 4) -alkyl, in which C4) -alkyl may be substituted by hydroxy,
  • R 7 is (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl or phenyl
  • R 8 is hydrogen or (C 1 -C 6 ) -alkyl
  • R 9 is hydrogen, (C 1 -C 6 ) -Alkyl or (C 3 -C 7 ) -cycloalkyl
  • R 10 is (Ci-C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl or phenyl, is CR 4 or N, wherein R 4 is hydrogen, (C 1 -C 4 ) -alkyl, (C 3 -C 7 ) -cycloalkyl or 3 to 7-membered heterocyclyl, wherein (C 1 -C 4 ) -alkyl having 1 to 3 substituents selected independently of one another the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy, (Ci-C4)
  • Di- (C 1 -C 4) -alkylamino in which mono- (C 1 -C 4) -alkylamino and di- (C 1 -C 4) -alkylamino in turn have 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl and phenyl in which 4- to 7-membered heterocyclyl may in turn be substituted by 1 or 2 substituents independently of one another selected from the group of fluoro, (C 1 -C 4) -alkyl, hydroxyl, oxo and (C 1 -C 4) -alkoxy, in which (C 1 -C 4) -alkyl in turn contains 1 or 2 substituents independently of one another selected from the group of fluorine, trifluoromethyl, hydroxy,
  • Trifluoromethoxy and (Ci-C4) alkoxy may be substituted, or
  • R 3 and R 4 together with V and W to which they are attached form a 4- to 7-membered heterocyclyl ring wherein the 4- to 7-membered heterocyclyl ring is substituted with (C 1 -C 4) -alkyl can
  • R 1 is hydrogen or fluorine
  • R 2 is (C 1 -C 6 ) -alkyl or benzyl, where (C 1 -C 6 ) -alkyl is substituted by a substituent trifluoromethyl, where (C 1 -C 6) -alkyl having 1 to 3 Substituents fluorine may be substituted, and wherein benzyl is substituted by 1 to 3 substituents fluorine, with the proviso that when V is N, W is CR, with the proviso that when W is N, V is CR 3 , and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-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 following compounds 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 of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid formic acid, acetic acid, trifluoro
  • 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 1 to 16 carbon atoms, for example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • 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
  • 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 where coordination with water occurs. 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 atropisomers).
  • 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 encompasses all suitable isotopic variants of the compounds according to 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 distribution of the drug in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
  • the 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.
  • iso- Topical 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 appropriate 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).
  • alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms.
  • alkyl radical having 1 to 4 carbon atoms.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated carbocycle having 3 to 7 ring carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert. Butoxy.
  • Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group. Examples which may be mentioned by way of example include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert. Butoxycarbonyl.
  • Heterocyclyl in the context of the invention is a saturated heterocycle having a total of 4 to 7 ring atoms, which contains one or two ring heteroatoms from the series N, O and / or S and is linked via a ring carbon atom or optionally a ring nitrogen atom.
  • Examples which may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.
  • Preferred are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • heterocycle monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine.
  • An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred.
  • V is CR 3 or N
  • R 3 is hydrogen, trifluoromethyl, (Ci-C 6) -alkyl, (C 3 -C 6) cycloalkyl, (Ci-C4) - alkoxycarbonyl, phenyl, pyridyl, -NR 5 R 6, -S (0) n is R 7 or -SO 2 NR 8 R 9 , wherein (Ci-C6) alkyl having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, trifluoromethoxy, (Ci-C i) alkoxy, methylamino, ethylamino , Dimethylamino, diethylamino, phenoxy, azetidinyl, pyrrolodinyl, piperidinyl, morpholinyl, piperazinyl and pyrazolyl may be substituted, wherein pyrazolyl in turn may be substituted with 1 or 2 substituents independently selected from the group of fluoro,
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl in turn may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, trifluoromethoxy, methoxy and ethoxy,
  • R 6 is (C 1 -C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, phenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dioxotetrahydrothiolanyl, piperidinyl, tetrahydropyranyl, in which phenyl is in turn independently selected with 1 or 2 substituents from the group of fluorine, chlorine, methyl, ethyl, methoxy, ethoxy and methylcarbonylamino, or R 5 and R 6 together with the nitrogen atom to which they are bonded form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl or dioxothiomorpholinyl ring, wherein the piperazinyl ring on the nitrogen may be substituted with ethyl wherein ethyl is substitute
  • R 7 is (C 1 -C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl, is hydrogen, methyl or ethyl, R 9 is hydrogen, methyl or ethyl; W is CR 4 or N, wherein
  • R 4 is hydrogen, (C 1 -C 4 ) -alkyl, cyclopropyl, cyclobutyl or cyclopentyl, in which (C 1 -C 4) -alkyl with trifluoromethyl, hydroxy, hydroxycarbonyl,
  • Methoxycarbonyl, ethoxycarbonyl, methylamino, ethylamino, dimethylamino or diethylamino may be substituted, wherein methylamino, ethylamino, dimethylamino and diethylamino may be substituted by phenyl, R 1 is hydrogen,
  • R 2 is 2-fluorobenzyl, provided that when V is N, W is CR 4 , with the proviso that when W is N, V is CR 3 , and their salts, solvates and solvates salts.
  • Particularly preferred in the context of the present invention are compounds of the formula (I) in which
  • U is S, V is CR 3 or N, where R 3 is hydrogen, trifluoromethyl, (C 1 -C 6) -alkyl, cyclopropyl, cyclohexyl, methoxycarbonyl, phenyl, pyridyl, -NR 5 R 6 , -S (0) n is R 7 or -SO 2 NR 8 R 9 , in which (C 1 -C 6) -alkyl may be substituted by trifluoromethyl, (C 1 -C 4) -alkoxy, methylamino, ethylamino, dimethylamino, diethylamino, phenoxy, pyrrolodinyl or pyrazolyl, wherein pyrazolyl in turn may be substituted with 1 or 2 substituents independently selected from the group consisting of methyl and ethyl, wherein phenyl and pyridyl may be substituted with 1 or 2 substituents independently selected from the group flu
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl may in turn be substituted by hydroxyl,
  • R 6 is (C 1 -C 4) -alkyl, cyclohexyl, phenyl or dioxotetrahydrothiolanyl, in which phenyl in turn may be substituted by methoxy, ethoxy or methylcarbonylamino, or
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperazinyl or morpholinyl ring in which the piperazinyl ring on the nitrogen is substituted by ethyl, in which ethyl is substituted by hydroxy,
  • R 7 is (C 1 -C 4 ) -alkyl or cyclohexyl
  • R 8 is hydrogen, methyl or ethyl
  • R 9 is hydrogen, methyl or ethyl, CR 4 or N, wherein
  • R 4 is hydrogen, (C 1 -C 4 ) -alkyl or cyclopropyl, in which (C 1 -C 4) -alkyl or methylamino may be substituted, wherein methylamino may be substituted with phenyl,
  • R is hydrogen
  • R 2 is 2-fluorobenzyl, provided that when V is N, W is CR, with the proviso that when W is N, V is CR 3 , and their salts, solvates and solvates of the salts ,
  • R 1 is hydrogen, and their salts, solvates and solvates of the salts.
  • R 2 is 2-fluorobenzyl, and their salts, solvates and solvates of the salts. Particularly preferred in the context of the present invention are also compounds of the formula (I) in which
  • U is S, and their salts, solvates and solvates of the salts.
  • V is N, and their salts, solvates and solvates of the salts.
  • R 3 is hydrogen, trifluoromethyl, (C 1 -C 6) -alkyl, cyclopropyl, cyclohexyl, methoxycarbonyl, phenyl, pyridyl, -NR 5 R 6 , -S (O) n R 7 or -SO 2 NR 8 R 9 in which (C 1 -C 6) -alkyl with trifluoromethyl, (C 1 -C 4) -alkoxy, methylamino, ethylamino,
  • pyrazolyl Dimethylamino, diethylamino, phenoxy, pyrrolodinyl or pyrazolyl, in which pyrazolyl may in turn be substituted with 1 or 2 substituents independently selected from the group consisting of methyl and ethyl, wherein phenyl and pyridyl having 1 or 2 substituents independently selected from the group fluorine , Chloro, methyl, methoxy and ethoxy, and wherein n is a number 1 or 2,
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl may in turn be substituted by hydroxyl,
  • R 6 is (C 1 -C 4) -alkyl, cyclohexyl, phenyl or dioxotetrahydrothiolanyl, in which phenyl in turn may be substituted by methoxy, ethoxy or methylcarbonylamino, or
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperazinyl or morpholinyl ring in which the piperazinyl ring on the nitrogen is substituted by ethyl, in which ethyl is substituted by hydroxy,
  • R 7 is (C 1 -C 4 ) -alkyl or cyclohexyl
  • R 8 is hydrogen, methyl or ethyl
  • R 9 is hydrogen, methyl or ethyl
  • W is N, and their salts, solvates and solvates of the salts.
  • R 4 is hydrogen, (C 1 -C 4 ) -alkyl or cyclopropyl, in which (C 1 -C 4) -alkyl or methylamino may be substituted, in which methylamino may be substituted by phenyl, and their salts, solvates and solvates of the salts.
  • 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) in which R 1 and R 2 each have the meanings given above, in an inert solvent in the presence of a suitable base and a suitable coupling reagent with a compound of the formula (III)
  • Inert solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1, 2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrogen halides such as dichloromethane, trichloromethane, Tetrachloromethane, trichlorethylene, chlorobenzene or 1, 2-dichlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acet
  • N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride EDC
  • N, N-diisopropylethylamine or O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) in combination with 4-methylmorpholine.
  • the reaction (II) + (III) -> (I) is generally carried out in a temperature range from 0 ° C to + 140 ° C, preferably carried out in a temperature range from + 20 ° C to + 60 ° C.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the compounds of the formula (II) are known from the literature (cf., for example, WO 2007/124854), and can be prepared in analogy to processes known from the literature.
  • Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular those listed under R 3 and R 4 , starting from the compounds of the formula (I) obtained by the above methods.
  • transformations are carried out as described in the present experimental part, according to customary methods known to the person skilled in the art, and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, eliminations, alkylation, amination, esterification, ester cleavage, Etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protecting groups.
  • reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, eliminations, alkylation, amination, esterification, ester cleavage, Etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protecting groups.
  • the compounds of the invention act as stimulators of soluble guanylate cyclase and possess valuable pharmacological, and are 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 by direct stimulation of soluble guanylate cyclase and an intracellular cGMP increase.
  • the compounds according to the invention enhance the action of substances which increase cGMP levels, such as, for example, EDRF (endothelium-derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • the compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, acute and chronic heart failure, heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, arrhythmias of the atria and the chambers and Transient disorders such as atrio-ventricular blockades grade I-III (AB block I-III), 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, aortiti
  • cardiac insufficiency also encompasses 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, valvular heart failure, cardiac valvulopathy, mitral valve stenosis, mitral valve insufficiency, Aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid regurgitation, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure.
  • ischemic cardiomyopathy dilated cardiomyopathy
  • the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and combined hyperlipidemias 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, gangrenous, 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 renal 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 others Forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg cigarette smoke-induced pulmonary emphysema) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory tract syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • pulmonary fibrosis pulmonary emphysema
  • CF cystic fibrosis
  • the compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO /
  • 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. They 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 conditional sexual dysfunction
  • 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 suitable 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 disorders of the eye.
  • 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 procedures), nevi, diabetic retinopathy and proliferative vitroretinopathy.
  • 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 diabetes, 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.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disease, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.
  • 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, ischemia, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.
  • 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 ,
  • 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 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 are: organic nitrates and NO donors, such as, for example, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • sildenafil, vardenafil and tadalafil inhibitors of phosphodiesterases 1, 2 and / or 5 inhibitors such as sildenafil, vardenafil and tadalafil
  • antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances
  • antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, endothelin antagonists, renin Inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics
  • lipid metabolism-altering agents by way of example and with preference from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, by way of example and preferably, HMG-
  • 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.
  • 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 by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • 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 blocker, beta-receptor blocker, mineralocorticoid receptor - understood 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.
  • 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 administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, 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 or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of 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 preferably spironolactone or eplerenone.
  • a diuretic such as by way of example and preferably furosemide.
  • 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, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol Abso ⁇ tionhemmer, polymeric Benklareadsorber, bile acid Reabso ⁇ tionshemmer, lipase inhibitors and the lipoprotein (a) understood antagonists.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol Abso ⁇ tionhemmer
  • polymeric Benklareadsorber bil
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • T3 3,5,3'-triiodothyronine
  • CGS 23425 CGS 23425
  • 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, rosuvastat
  • 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.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • 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.
  • 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 according to the invention quickly and / or modified donating application forms, the Compounds according to the invention in crystalline and / or amorphised 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) in the oral cavity quickly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragées, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • compositions 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.
  • adjuvants include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers For example, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example, antioxidants such as
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Instrament Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1,8 ⁇ 50 x 1mm; 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; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 210 - 400 nm.
  • 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
  • gradient 0.0 min 95% A - 0.15 min 95% A - 8.0 min 5% A - 9.0 min 5% A
  • flow 40 ml / min
  • UV detection DAD, 210 - 400 nm).
  • 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
  • gradient 0.0 min 95% A - 0.15 min 95% A - 8.0 min 5% A - 9.0 min 5% A
  • flow 40 ml / min
  • UV detection DAD, 210 - 400 nm).
  • Example 1 Exemplary embodiments: Example 1
  • Example 1A 500 mg (1.843 mmol) of Example 1A were initially charged in 5 ml of dichloromethane and 5 ml of dimethylformamide and then with 312 mg (2.212 mmol) of 2-amino-5-cyclopropyl-l, 3,4-thiadiazole, 530 mg (2.765 mmol) - (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.963 ml (5.530 mmol) of ⁇ , ⁇ -diisopropylethylamine. Thereafter, it was stirred for 1.5 hours at room temperature. It was then diluted with water and dichloromethane and the phases separated.
  • the aqueous phase was extracted twice with dichloromethane and the combined organic phases were concentrated. Further purification was carried out by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 146 mg of the target compound were obtained (19% of theory).
  • the multi-well plate was covered and shaken at room temperature for 18 h. It was then filtered off and the filtrate purified directly via preparative LC-MS method 2 or 3.
  • the product-containing fractions were concentrated by means of a centrifugal dryer in vacuo. The residue of the individual fractions was dissolved in 0.6 ml of DMSO and combined. Subsequently, the solvent was completely evaporated in a centrifugal dryer. There were obtained 4.2 mg (10% of theory) of the title compound.
  • the multi-well plate was covered and shaken at room temperature for 18 h. It was then filtered off and the filtrate was purified directly via preparative LC-MS according to Method 2 or 3.
  • the product-containing fractions were concentrated by means of a centrifugal dryer in vacuo. The residue of the individual fractions was dissolved in 0.6 ml of DMSO and combined. Subsequently, the solvent was completely evaporated in a centrifugal dryer. 5.80 mg (12% of theory) of the title compound were obtained.
  • 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% (IC50 value).
  • the standard application volume is 5 ⁇ , the DMSO content in the bath solution corresponds to 0.1%.
  • the cellular activity of the compounds of the invention is measured on a recombinant guanylate cyclase reporter cell line as described in F. Wunder et al., Anal. Biochem.339, 104-112 (2005).
  • 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
  • Physiotel® receivers connected to 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.
  • the experimental animals are kept individually in macroion cages type 3 after transmitter implantation. You have free access to standard food and water.
  • the day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.
  • the TAH 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.
  • pentobabital Nembutal, Sanofi: 50 mg / kg i.p.
  • 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 prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)
  • a solvent-treated group of animals is used as a control.
  • 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 Activity
  • the measured value acquisition is repeated computer-controlled in 5-minute intervals.
  • the absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).
  • test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.
  • the collected individual data are sorted with the analysis software (DATAQUEST TM A.RT. TM ANALYSIS).
  • the blank value is assumed here 2 hours before application, so that the selected data record covers the period from 7:00 am on the day of the experiment to 9:00 am on 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 so 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. literature
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. i.v. -Solution:
  • the compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution).
  • a physiologically acceptable solvent e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

La présente invention concerne de nouveaux thiazolamides et thiadiazolamides substitués, leur procédé de fabrication, leur utilisation seuls ou en combinaisons pour le traitement et/ou la prophylaxie de maladies, ainsi que leur utilisation pour fabriquer des médicaments destinés au traitement et/ou à la prophylaxie de maladies, notamment au traitement et/ou à la prophylaxie de maladies cardiovasculaires.
PCT/EP2017/050311 2016-01-15 2017-01-09 Thiazolamides et thiadiazolamides substitués et leur utilisation WO2017121693A1 (fr)

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Citations (17)

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