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EP1814872A1 - Substituted [(phenylethanoyl)amino] benzamides and the use thereof in the treatment of inflammatory and cardio-vascular diseases - Google Patents

Substituted [(phenylethanoyl)amino] benzamides and the use thereof in the treatment of inflammatory and cardio-vascular diseases

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Publication number
EP1814872A1
EP1814872A1 EP05813330A EP05813330A EP1814872A1 EP 1814872 A1 EP1814872 A1 EP 1814872A1 EP 05813330 A EP05813330 A EP 05813330A EP 05813330 A EP05813330 A EP 05813330A EP 1814872 A1 EP1814872 A1 EP 1814872A1
Authority
EP
European Patent Office
Prior art keywords
benzothien
substituents
alkyl
amino
naphth
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05813330A
Other languages
German (de)
French (fr)
Inventor
Ulf Brüggemeier
Petros Gatsios
Mark Meininghaus
Leila Telan
Elisabeth Woltering
Martina Wuttke
Hartmut Beck
Nils Griebenow
Frank. SÜSSMEIER
Johannes KÖBBERLING
Axel Kretschmer
Niels Svenstrup
Marcus Bauser
Wahed Moradi
Siegfried Zaiss
Claudia Hirth-Dietrich
Barbara Albrecht
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Healthcare AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1814872A1 publication Critical patent/EP1814872A1/en
Withdrawn legal-status Critical Current

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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

  • the invention relates to substituted [(phenylethanoyl) amino] benzamides and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of inflammatory diseases, such as e.g. Dermal, respiratory and cardiovascular disorders, e.g. Arteriosclerosis and coronary heart disease.
  • inflammatory diseases such as e.g. Dermal, respiratory and cardiovascular disorders, e.g. Arteriosclerosis and coronary heart disease.
  • WO 02/070471 claims structurally similar compounds as factor Xa and factor VIIa inhibitors, inter alia for the treatment of thrombosis, inflammatory diseases and arteriosclerosis.
  • WO 98/47885 claims structurally similar compounds as combined 5HT1A, 5HT1B and 5HTl D receptor antagonists for the treatment of central nervous system disorders.
  • Interleukin-8 belongs to the class of pro-inflammatory chemokines with the ability to attract leukocytes. The role of IL-8 in various inflammatory diseases is well described. The biological effects of IL-8 are mediated via binding to two specific receptors, CXCR1 and CXCR2, on the cell surface of target cells (Baggiolini M, Annu Rev Immunol 1997, 15, 675-705, Baggiolini M, J Int Med 2001 , 250, 91-104).
  • the inflammatory component in the pathophysiology of arteriosclerosis is generally recognized. This is also triggered by inflammatory cells (T cells, monocytes, macrophages) and secreted mediators (cytokines, chemokines) (Libby P., Nature 2002, 420, 868-874, Boisvert WA, Trends Cardiovasc Med 2004, 14, 7 -18).
  • T cells inflammatory cells
  • cytokines, chemokines secreted mediators
  • the inflammatory vascular changes are caused by the reaction of migrating monocytes with pathogenic lipoproteins in the arterial wall.
  • An antagonist of the IL-8 receptor would stop macrophage accumulation in the lesions and would thus be useful for the treatment of arteriosclerosis.
  • IL-8 receptor antagonists could find application in any disease involving activated monocytes, macrophages, or lymphocytes, since all of these cells express the receptor.
  • the invention relates to compounds of the formula
  • Y is a bond, methanediyl, sulfur or oxygen
  • R 1 is biphenyl-4-yl, where in biphenyl-4-yl 1 to 3 carbon atoms may be replaced by nitrogen,
  • X is N, O or S
  • the phenyl ring is attached via the 4 or 5 position if the five-membered ring is bonded to the carbon atom via the 2-position, or the phenyl ring is bonded via the 5-position if the five-membered ring is bonded to the carbon atom via the 3-position .
  • W is C or N
  • V is N, O or S
  • * is the point of attachment to the carbon atom, and the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
  • the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
  • radicals R 1 can be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C O - alkoxy, Ci-C ⁇ alkylamino, hydroxycarbonyl, Ci-C ⁇ alkoxycarbonyl, aminocarbonyl, C 1 - C ⁇ alkylaminocarbonyl, Ci-C ö alkylcarbonyl and Ci-C ⁇ -Alkylcarbonylammo,
  • R 2 is hydrogen, C 1 -C 6 -alkyl or C 3 -C 7 -cycloalkyl
  • R 3 is C 3 -C 7 -cycloalkyl or optionally substituted by up to five fluorine-substituted C 1 -C 4 -alkyl,
  • R 7 is a group of the formula
  • R 4, R 5 and R 6 gen independently hydrogen, hydroxy, amino, Halo ⁇ , cyano, Trifiuormethyl, trifluoromethoxy, Ci-C ⁇ alkyl, C 1 -Co -alkoxy, Ci-C ö alkylamino, C 3 - C 7 -cycloalkyl, 5- to 7-membered heterocyclyl, Ce- Qo-aryl, 5- or 6-membered heteroaryl, hydroxycarbonyl, C 1 -C 6 -cycloalkyl,
  • cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino,
  • R 4 and R 5 are attached to adjacent carbon atoms and form a -O-CH 2 -CH 2 -O- bridge,
  • heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C 6 alkyl, Ci-C 6 alkoxy and C 1 -C 6 -alkylamino,
  • Compounds of the invention are the compounds of the formula (Ia) and (I) and their salts, solvates and solvates of the salts, as well as those of the formula (Ia) and (I), hereinafter referred to as the exemplary embodiment (e) compounds and salts thereof , Solvates and solvates of the salts, as far as the compounds of formula (Ia) and (I) mentioned below are not already salts, solvates or solvates of the salts.
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to 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, 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, acetic acid, trifluoroacetic acid, propionic 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 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.
  • the free base of the salts of the compounds according to the invention can be obtained, for example, by addition of an aqueous base, for example dilute sodium hydroxide solution, and subsequent extraction with a solvent by methods known to the person skilled in the art.
  • an aqueous base for example dilute sodium hydroxide solution
  • a solvent for example dilute sodium hydroxide solution
  • Alkylcarbonyl and Alkylcarbonylamino stand for a linear or branched alkyl radical with usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl Butyl, n-pentyl and n-hexyl.
  • Alkoxy is exemplified and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N Dimethylamino, NN
  • Alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkoxycarbonyl is by way of example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, the alkyl substituents independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n -Propylaminocarbonyl, isopropylaminocarbonyl, tert -butylaminocarbonyl, n -pentylaminocarbonyl, n -hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N -diethylaminocarbonyl, N -ethyl-N-methylaminocarbonyl, N -methyl-Nn-propylaminocarbonyl, N -Isopropyl-Nn-propylaminocarbonyl, N-tert-but
  • C 1 -C 3 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylcarbonyl is by way of example and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.
  • Alkylcarbonylamino is by way of example and preferably methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
  • Cycloalkyl is a cycloalkyl group having usually 3 to 7, preferably 5 to 7 carbon atoms, by way of example and preferably cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Aryl is a mono- or bicyclic aromatic radical having generally 6 to 10 carbon atoms, by way of example and preferably aryl are phenyl and naphthyl.
  • Heteroaryl is an aromatic, monocyclic radical having usually 5 or 6 ring atoms and up to 4, preferably up to 2 heteroatoms from the series S, O and N, where a nitrogen atom can also form an N-oxide, by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.
  • Heterocyclyl is a monocyclic, heterocyclic radical having usually 5 to 7 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO 2 , where a nitrogen atom also can form an N-oxide.
  • the heterocyclyl radicals may be saturated or partially unsaturated.
  • Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • radicals are substituted in the compounds according to the invention, the radicals may, unless otherwise specified, be mono- or polysubstituted or differently substituted. A substitution with up to three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • Preferred compounds of the formula (Ia) are those of the formula
  • Y is a bond or methanediyl
  • R 1 is biphenyl-4-yl, where in biphenyl-4-yl 1 to 3 carbon atoms may be replaced by nitrogen,
  • X is N, O or S
  • the phenyl ring is attached through the 4 or 5 position when the five-membered ring is attached to the carbon atom through the 2-position, or the phenyl ring is attached through the 5-position Position is bound when the five-membered ring is bonded to the carbon atom via the 3-position,
  • W is C or N
  • V is N, O or S
  • the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
  • the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
  • radicals R 1 may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C ö alkyl, Q-Ce -
  • R 2 is hydrogen, C 1 -C 6 -alkyl or C 3 -C 7 -cycloalkyl
  • R 3 is C 3 -C 7 -cycloalkyl or optionally substituted by up to five fluorine-substituted Ci-Gj-alkyl,
  • R 4 , R 5 and R 6 independently of one another represent hydrogen, hydroxyl, amino, halogen, cyano,
  • Cycloalkyl 5- to 7-membered heterocyclyl, C ⁇ -Cio-aryl, 5- or 6-membered heteroaryl,
  • Ci-C ö alkoxycarbonyl aminocarbonyl, Ci-C ⁇ -alkylaminocarbonyl, Ci-C ö alkylcarbonyl or Ci-C ⁇ -Alkylcarbonylamino represents,
  • cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, Trifluor ⁇ methoxy, Ci-C ⁇ -alkyl, Ci -C ö alkoxy, Ci-C 6 -alkylamino, hydroxycarbonyl, Ci-C ⁇ - alkoxycarbonyl, aminocarbonyl, Ci-C ⁇ alkylaminocarbonyl, Cj-Ce-alkylcarbonyl, and
  • Y is a bond or methanediyl
  • R 1 is biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenylthien-2-yl, 5-phenyl-furan -2-yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1-benzothiene 6-yl, 1-benzofuran-2-yl or 1-benzofuran-3-yl, wherein biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenylthien-2-yl, 5-phenyl-furan-2 -yl, naphth-1-yl, naphth-2-yl, quinolin-6-y
  • Ci-C ⁇ -alkyl C 1 -Ce- alkoxy, Ci-C ö alkylamino, hydroxycarbonyl, Ci-C ⁇ -alkoxycarbonyl, aminocarbonyl, Ci-C ⁇ -alkylaminocarbonyl, Ci -C ö alkylcarbonyl and Ci-C ö alkylcarbonylamino,
  • R 2 is 6 alkyl, hydrogen or C r C,
  • R 3 is C 3 -C 7 -cycloalkyl or optionally C 1 -C 4 -alkyl substituted with up to five fluorine,
  • R 4 , R 5 and R 6 independently of one another represent hydrogen, hydroxyl, amino, halogen, cyano,
  • Cycloalkyl 5- to 7-membered heterocyclyl, C ⁇ -Cio-aryl, 5- or 6-membered heteroaryl, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, Q-
  • cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of hydroxyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, Ci-C 6 -alkylamino, hydroxycarbonyl, C r C 6 -
  • Y is a bond or methanediyl
  • R 1 is biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenylthien-2-yl, 5-phenyl-furan -2-yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1-benzothiene 6-yl, 1-benzofuran-2-yl or 1-benzofuran-3-yl, wherein biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenylthien-2-yl, 5-phenyl-furan-2 -yl, naphth-1-yl, naphth-2-yl, quinolin-6-y
  • R 2 is 6 alkyl, hydrogen or C r C,
  • R 3 is C 3 -C 7 -cycloalkyl or optionally substituted by up to five fluorine-substituted CrQ-alkyl,
  • R 4, R 5 and R 6 fluoromethoxy independently hydrogen, halogen, cyano, trifluoromethyl, Tri ⁇ , Ci-C 6 alkyl, C 3 -C 7 -cycloalkyl, hydroxycarbonyl, Ci-C ö alkoxycarbonyl, aminocarbonyl, Ci -C ä alkylaminocarbonyl, Ci-C ⁇ -alkylcarbonyl or Ci-C ö -Alkylcarb- carbonylamino group,
  • cycloalkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Q-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, Ci -C ⁇ -alkylamino, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl and C 1 -C 6 -alkylcarbonylamino,
  • Y is a bond or methanediyl
  • R 1 is biphenyl-4-yl, 5-phenylthien-2-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl or 1-benzofuran-2-yl,
  • biphenyl-4-yl and naphth-2-yl may be substituted by 1 to 2 substituents, where the substituents are selected independently of one another from the group consisting of fluorine, chlorine, methoxy and ethoxy,
  • R 2 is hydrogen
  • R 3 is methyl, ethyl or isopropyl
  • R 4 , R 5 and R 6 independently of one another represent hydrogen or halogen
  • R 1 is biphenyl-4-yl, 5-phenylthien-2-yl, naphth-2-yl, quinolin-6-yl, Benzothien-2-yl or l-benzofuran-2-yl, wherein biphenyl-4-yl and naphth-2-yl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of fluorine, chlorine , Methoxy and ethoxy.
  • R 4 , R 5 and R 6 are independently hydrogen or halogen.
  • the invention further provides a process for the preparation of the compounds of formula (Ia), wherein
  • R 1 has the meaning given above
  • R 1 and R 2 have the abovementioned meaning
  • Y, R 3 and R 7 have the abovementioned meaning
  • X 1 is halogen, preferably iodine or bromine, or hydroxy
  • the reaction according to method [A] is generally carried out under Suzuki reaction conditions in inert solvents in the presence of a catalyst, optionally in the presence of a satzreagenzes Zu ⁇ , preferably in a temperature range from room temperature to 130 0 C at normal Kotha, K., Lahiri, D. Kashinath, Tetrahedron 2002, 58 (48), 9633-9695 and N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483).
  • catalysts are conventional palladium catalysts for Suzuki reaction conditions, preferably catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphmpalladium (O), palladium (II) acetate, l, r-bis [(diphenylphosphino) ferrocen] palladium II chloride (1: 1) complex with dichloromethane.
  • catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphmpalladium (O), palladium (II) acetate, l, r-bis [(diphenylphosphino) ferrocen] palladium II chloride (1: 1) complex with dichloromethane.
  • Additional reagents are for example potassium acetate, cesium, potassium or sodium carbonate, Ba ⁇ riumhydroxid, potassium tert-butoxide, cesium fluoride or potassium phosphate carried out, preference is given to additional reagents such. Potassium acetate and / or aqueous sodium carbonate solution.
  • Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or other solvents, such as nitrobenzene, dimethylformamide, dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone.
  • Preferred solvents are eg Dimethylformamide, dimethylacetamide, dimethylsulfoxide or 1,2-dimethoxyethane.
  • reaction according to process [B] is carried out, if X 1 is halogen, generally in inert solvents, in the presence of a base, preferably in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, is preferred Tetrahydrofuran or methylene chloride.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile
  • bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, be ⁇ preferred is diisopropylethylamine.
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, be ⁇ preferred is diisopropylethylamine.
  • reaction according to process [B] is carried out, if X 1 is hydroxy, generally in inert solvents, in the presence of dehydrating reagents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to room temperature at normal pressure.
  • dehydrating reagents examples include carbodiimides, such as N, N'-diethyl, NN'-dipropyl, NN'-diisopropyl, NN'-dicyclohexylcarbodiimide, N- (3-dimethylamino) isopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2- Oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • the condensation is carried out with diisopropylethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, etromonethane, dioxane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
  • the compounds of the formula (ET) are known or can be prepared by adding compounds of the formula
  • R 2 has the meaning given above, with compounds of formula (V) according to method [B].
  • the compounds of the formula (VI) are known or can be prepared by the Ver ⁇ binding of the formula
  • R 2 has the meaning given above, and
  • X 2 is halogen, preferably iodine or bromine
  • the reaction is generally carried out in inert solvents, if appropriate in the presence of a base, if appropriate in the presence of potassium iodide, preferably in a temperature range from room temperature to reflux of the solvents under atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran , Methylene chloride, acetone, 2-butanone, acetonitrile, dimethylformamide or 1,2-dimethoxyethane.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile,
  • bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride, DBU, preferably potassium tert-butoxide, cesium carbonate, DBU, sodium hydride, potassium carbonate or sodium carbonate.
  • the compounds of formula (VI) can be prepared by reacting the compound of formula (VII) with compounds of formula
  • R 2 has the meaning given above
  • the reaction is generally carried out in inert solvents, in the presence of a Redukti ⁇ onsffens, preferably in a temperature range from -20 0 C to reflux of the Wegsmit ⁇ tel at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or a mixture of alcohol and water, is preferred a mixture of methanol and water.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or a mixture of alcohol and water, is preferred a mixture of methanol and water.
  • Reducing agents are, for example, sodium borohydride or triacetoxyborohydride.
  • the compounds of the formula (IV) are known or can be prepared by reacting the compound of the formula (VI) with compounds of the formula (III) according to process [A].
  • the amide function of the compounds of the formulas (H) 3 (IV), (VI) and (VH) is optionally during the reactions with a polymeric carrier (eg rinkamide resin) or a protective group (eg 2, 4-dimethoxybenzyl) which is cleaved in the last stage according to conditions known to the person skilled in the art in order to obtain compounds of the formula (I).
  • a polymeric carrier eg rinkamide resin
  • a protective group eg 2, 4-dimethoxybenzyl
  • the compounds of the invention show an unpredictable, valuable pharmacological spectrum of action.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their action as DL-8 receptor antagonists.
  • the present invention further provides for the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably skin, respiratory and cardiovascular diseases, in particular arteriosclerosis.
  • diseases preferably skin, respiratory and cardiovascular diseases, in particular arteriosclerosis.
  • the compounds of the invention are suitable for the treatment and prevention of IL-8-triggered inflammatory processes, the skin diseases (eg psoriasis, (atopic) dermatitis, acne, eczema), respiratory diseases (eg asthma, bronchitis, chronic obstructive pulmonary disease , Respiratory distress syndrome), cardiovascular diseases (eg arteriosclerosis, dyslipidaemia, myocardial infarction, stroke, restenosis, reperfusion injury, thrombosis, ischaemia, coronary heart disease, pulmonary hypertension, left / right heart failure, arrhythmias, unstable angina pectoris) and infections (eg with plasmodia, hepatitis and herpes viruses), as well as arthritis (eg osteoarthritis, rheumatoid arthritis), osteoporosis, Crohn's disease, inflammatory bowel disease (eg ulcerative colitis), Alzheimer's disease, sepsis, Gingivitis, shocks (eg septic shock, endo
  • the compounds according to the invention can be used alone and if necessary also in combination with other active substances, in particular with anti-hyperlipidemic, anti-arteriosclerotic, anti-diabetic, anti-inflammatory or anti-hypertensive agents.
  • Examples include cholesterol synthesis inhibitors such as statins such as simvastatin, pravastatin and atorvastatin, antioxidants such as probucol, AGIl 067 and Bo653, PPAR modulators, fibrates such as gemfibrozil and fenofibrate, cholesterol absorption inhibitors such as ezetimibe, bile acid resins such as eg cholestyramine and colesevelam, acetylCoA acyltranferase (ACAT) inhibitors, cholesterol ester transfer protein (CETP) inhibitors, microsomal transfer protein (MTP) / apolipoprotein B- Secretion inhibitors, ileal bile acid transporter (IBAT) inhibitors, niacin and its slow-release forms, insulin (of animal, human or biotechnological origin and mixtures thereof), insulin sensitizers, calcium channel antagonists of, for example, dihydropyridine Type, diltiazeme type and verapamil type, ACE
  • Another object of the present invention is the use of Ver ⁇ compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned ge diseases.
  • Another object of the present invention is the use of Ver ⁇ compounds of the invention for the preparation of a medicament for the treatment and / or prophylaxis of Erkran ⁇ kung, in particular the aforementioned diseases.
  • Another object of the present invention are interleukin-8 receptor antagonists for the treatment and / or prophylaxis of heart failure.
  • Another object of the present invention is the use of an interleukin-8 receptor antagonist for the manufacture of a medicament for the treatment and / or prophylaxis of cardiac insufficiency.
  • Another object of the present invention is a method for the treatment and / or Pro ⁇ phylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of the compounds of the invention.
  • 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, na ⁇ sal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the prior art is capable of rapidly and / or modifying the compounds according to the invention which release the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, for example tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules in the oral cavity Pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • the oral application is preferred.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets to be applied
  • films / wafers or capsules to be applied
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (such as patches)
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries.
  • 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, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers ( for example, albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodec
  • a further subject of the present invention are medicaments which comprise at least one compound according to the invention, usually together with one or more inert, non-toxic compounds. rule, contain pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • FCS Fetal CaIf Serum Fetal Calf Serum
  • PBS Phosphate Buffered Saline Phosphate Buffered Sodium Chloride Solution
  • Method 2 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 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; Gradient: 0.0 min 90% A - »2.5 min 30% A -> 3.0 min 5% A -» 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O 0 C; UV detection: 210 nm.
  • Method 3 Instrument MS: Micromass TOF (LCT); Instrument HPLC: 2-column circuit, Waters2690; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 95% A ⁇ »1.8 min 25% A -» 1.9 min 10% A -> 2.0 min 5% A - »3.2 min 5% A; Oven: 4O 0 C; Flow: 3.0 ml / min; UV detection: 210 nm.
  • Method 4 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 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; Gradient: 0.0 min 90% A ⁇ > 2.5 min 30% A -> 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O 0 C; UV detection: 208-400 nm.
  • Method 5 Instrument MS: Waters ZQ 2000; Instrument HPLC: Agilent 1100, 2-column circuit, Autosampler: HTC PAL; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A - 0.1 min 95% A - 0.8 min 25% A - 0.9 min 5% A - 1.8 min 5% A - 1.81 min 100% A - 1.9 min 100% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.
  • Method 6 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 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; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A ⁇ »4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O 0 C; UV detection: 210 nm.
  • Method 7 Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm ⁇ 2 mm, 3.5 ⁇ m; Eluent A: 5 ml HCIO 4 / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.
  • Polymer-bound 2-iodo-5-nitrobenzamide (Polymer 1, Example 6A) is initially charged in a 2: 1 solvent mixture of dioxane and aqueous sodium carbonate solution. Add 10 equivalents of boronic acid and 0.1 equivalent of the Pd catalyst and stir at 8O 0 C overnight under argon. It is decanted off and washed three times with water, three times with DMF, twice with 0.1% sodium pyrrolidinethiocarbamate in a solvent mixture of THF and methanol (5: 1) and then alternately three times with methanol and DCM alternately. The polymer is then dried in vacuo.
  • Polymer 2 is added to a 2 molar tin dichloride solution in DMF (65 equivalents) and shaken overnight at RT. It is decanted off, washed three times each with DMF, methanol and DCM and dried in vacuo.
  • Polymer 3 is presented in DCM. Add 10 equivalents of DIEA and 5 equivalents of carbonic acid chloride and shake overnight at RT. It is decanted, washed three times with DMF and then three times with methanol and DCM and the polymer is dried in vacuo. It is mixed with a 2: 1 mixture of dioxane and a solution of 5 equivalents Ka ⁇ liumhydroxid in methanol and shaken overnight at RT. The polymer is filtered off and The polymer washes three times with water and DMF and then alternately three times with methanol and DCM. The polymer is dried in vacuo.
  • Polymer 4 is treated with concentrated TFA. It is allowed to stand for an hour and filtered from the polymer. Subsequently, the polymer is mixed with a 1: 1 mixture of TFA and DCM and allowed to stand again for one hour. It is again filtered from the polymer and the polymer is washed twice with the 1: 1 mixture of TFA and DCM. The combined filtrates are evaporated in vacuo and the crude product thus obtained is purified by preparative HPLC.
  • Non-commercially available 2- (het) arylacetic acids can be synthesized by lithiation with LDA or LiHMTS and subsequent alkylation with an alkyl halide, see Thompson, H.W .; Rashid, S.Y. J. Org. Chem. 2002, 67, 2813-2825.
  • the deprotected Rinc amide polymer is suspended in 20 ml DCM and 2.00 g (1.55 mmol, 2 equivalents) of DIEA and then 1.93 g (6.18 mmol, 2 equivalents) of 2-iodo-5-nitrobenzoic acid chloride (Example 2A) are added. It is shaken overnight at room temperature. It is then washed three times each with DMF, methanol and DCM. The resulting polymer 1 is dried in vacuo.
  • the preparation is analogous to the synthesis of the compound from Example 1 from the corresponding starting compounds.
  • the compound is prepared from quinoline-3-boronic acid and 2-iodo-5 - [(2- (3-fluorophenyl) butanoyl) amino] benzamide in 13.7 mg (23% of theory) yield in analogy to Example 1.
  • 2-iodo-5 - [(2- (3-fluorophenyl) butanoyl) amino] benzamide is prepared from 5-amino-2-iodobenzamide and 2- (3-fluorophenyl) butanoic acid under standard amide coupling conditions with HATU.
  • the compound is prepared from 4-amino-1, r: 4 ', l "-terphenyl-2-carboxamide and 2- (2-thienyl) - propionic acid in 26% yield in analogy to Example 1.
  • 4-Amino-1, r: 4 ', r ⁇ -terphenyl-2-carboxamide is prepared in analogy to the preparation of 5-amino-2- (1-benzothien-2-yl) benzamide (Example 7A and 8A).
  • the racemate is separated into the enantiomers.
  • Enantiomer separation gives 8 mg of enantiomer 37-2 from 20 mg of racemate.
  • Enantiomer separation gives 77 mg enantiomer 39-2 from 160 mg racemate.
  • the racemate is separated into the enantiomers.
  • CHO cells with mitochondrially localized aequorin are stably transfected with the human IL8B receptor and the G-alpha-16 protein.
  • Activation of the IL8B receptor with IL8 or an endogenous P2Y receptor with ATP leads to Ca 2+ release.
  • This intracellular Ca 2+ transient can be detected bioluminescently with mitochondrially localized aequorin.
  • IL8-induced Ca 2+ transients are inhibited by IL8B receptor antagonists. Substances that also inhibit ATP-induced Ca 2+ transients are nonspecific.
  • the IL8B receptor is activated by the addition of 25 ⁇ l of a 0.78-2.6nM IL8 solution in 2mM Ca-Tyrode / 0.1% BSA or the endogenous P2Y receptor is prepared by adding 25 ⁇ l of a 7.8-26 ⁇ M ATP solution in 2mM Ca. Tyrode activated. The bioluminescence is recorded at the same time. IC 50 values are calculated using dose-response curves using the Marquardt-Levenberg-Fit (Table A).
  • Test substances luminol (50 ⁇ M), Horse Radish Peroxidase (HRP; 1 U / ml) and recombinant human IL-8 (10-50 nM) are incubated with the PMN cell suspension and the emitted luminescence as RLU's (relative light units) in the luminometer measured immediately. This is considered a measure of the IL-8 induced ROS generation.
  • the area under the corresponding curve is used to determine the inhibitory activity and the half-maximal inhibitory concentration of the tested substances.
  • Cell culture CHO cells transfected with the human IL8 receptor B are cultured in DMEM medium with 10% FCS, penicillin (100 units / ml), streptomycin (100 ⁇ g / ml) and 0.4 mg / ml G418.
  • Membrane Preparation Cells are harvested subconfluently with trypsin and centrifuged at 500 xg for 5 min. The cell pellet is washed with PBS and then taken up in ice-cold assay buffer (50 mM Tris-HCl, 10 mM EDTA, 10 mM MgCl 2 , pH 7.4 including one time protease inhibitor cocktail (# 1873580, Roche)). Subsequently, the cells are homogenized with ice for 30 seconds on a polytron and centrifuged for 10 min at 500 xg at 4 0 C to remove the cell nuclei.
  • ice-cold assay buffer 50 mM Tris-HCl, 10 mM EDTA, 10 mM MgCl 2 , pH 7.4 including one time protease inhibitor cocktail (# 1873580, Roche)
  • the supernatant is then centrifuged at 100,000 xg (30 min, 4 0 C) and the membrane pellet resuspended in assay buffer.
  • the membrane preparation is frozen Kit ⁇ at -80 0 C and the protein content using the BCA assay (Pierce).
  • Receptor binding Receptor membranes (1 ⁇ g) are incubated with 0.2 nM 125 I labeled IL8 (Amersham) for 2 h in assay buffer at room temperature in the presence and absence of test substance. Receptor-bound EL8 is measured by adding WGA SPA beads (Amersham) in a Wallac scintillation counter.
  • Substances are administered 30 min (po) [10 ml / kg] or 10 min (iv) [5 ml / kg] before EL-8 stimulation.
  • the percentage of neutrophils in the total cell number is determined, the IL-8-stimulated control group and for the substances, substance-treated animals for the placebo-treated unstimulated "control group.
  • the induced by administration of substance, the percentage inhibition as well as the significance (t-test) of the IL- 8 induced neutrophil migration is calculated relative to the IL-8 treated control animals.
  • IL-8 receptor antagonists To determine the anti-atherosclerotic effect of IL-8 receptor antagonists, generally accepted animal models are used in research, such as the ApoE knockout mouse (Red ⁇ dick, RL, et al., Arterioscler, Thromb., 1994, 14, 141-147). or the LDL receptor knockout mouse (Ishibashi, S., et al., Proc Natl Acad., USA 1993, 91, 4431-4435).
  • LAD left descending coronary artery
  • a thread PROLENE 1 metric 5-0 ETHICONlH
  • EL-8 receptor antagonists begins 1-2 days after the LAD occlusion.
  • Periodic ECG and echocardiographic examinations are performed over several weeks or months to analyze the development of heart failure, with and without 11-8 receptor antagonists, in the rats.
  • Blood samples are taken regularly to determine biomarkers (eg, BNP) that are a clinically accepted measure of the development of cardiac insufficiency.
  • biomarkers eg, BNP
  • the contractility of the heart is determined with a milliliter pressure catheter in vivo, the hearts are removed and histologically characterized.
  • Other in vivo in vivo assay systems are known in the literature: Braun A. et al., Circ. Res., 90, 270-6 (2002); Wang Q.-D.
  • the substances according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Germany) and 2 mg of magnesium stearate.
  • the mixture of the compound of Example 1, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
  • Example 1 The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring.
  • the solution is sterile-filtered (pore diameter 0.22 ⁇ m) and filled under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

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Abstract

The invention relates to substituted [(phenylethanoyl)amino] benzamides and to methods for the production thereof in addition to the use thereof in the production of medicaments for the treatment of and/or prophylaxis of illnesses, particularly inflammatory diseases such as diseases of the skin, respiratory passages and cardio-vascular diseases such as arteriosclerosis and coronary heart diseases.

Description

SUBSTITUIERTE N ( PHENYLETHANOYL) AMINO ! BENZAMIDE UND DEREN VERWENDUNG ZUR BEHANDLUNG VON INFLAMMATORISCHEN -SOWIE HERZ-KREISLAUF-ERKRANKUNGENSUBSTITUTED N (PHENYLETHANOYL) AMINO! BENZAMIDES AND THEIR USE FOR THE TREATMENT OF INFLAMMATORY AND HEART CIRCULAR DISEASES
Die Erfindung betrifft substituierte [(Phenylethanoyl)amino]benzamide und Verfahren zu ihrer Herstellung sowie ihre Verwendung zur Herstellung von Arzneimitteln zur Behandlung und/oder Prophylaxe von Krankheiten, insbesondere von inflammatorischen Erkrankungen, wie z.B. Haut-, Atemwegs- und Herz-Kreislauf-Erkrankungen, wie z.B. Arteriosklerose und koronare Herzerkran¬ kungen.The invention relates to substituted [(phenylethanoyl) amino] benzamides and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of inflammatory diseases, such as e.g. Dermal, respiratory and cardiovascular disorders, e.g. Arteriosclerosis and coronary heart disease.
WO 02/070471 beansprucht strukturell ähnliche Verbindungen als Faktor Xa und Faktor VIIa In¬ hibitoren unter anderem zur Behandlung von Thrombose, inflammatorischen Erkrankungen und Arteriosklerose.WO 02/070471 claims structurally similar compounds as factor Xa and factor VIIa inhibitors, inter alia for the treatment of thrombosis, inflammatory diseases and arteriosclerosis.
WO 98/47885 beansprucht strukturell ähnliche Verbindungen als kombinierte 5HT1A, 5HT1B und 5HTl D Rezeptor Antagonisten zur Behandlung von Erkrankungen des zentralen Nervensystems.WO 98/47885 claims structurally similar compounds as combined 5HT1A, 5HT1B and 5HTl D receptor antagonists for the treatment of central nervous system disorders.
Die Attraktion von Leukozyten an einen spezifischen Ort der Vaskulatur und die darauffolgende Einwanderung / Migration in das darunter liegende, geschädigte Gewebe sind Grundlage bei der Entstehung der Entzündung. Neben der Expression verschiedenartiger Adhäsionsmoleküle (Selek- tine, ICAM, VCAM) auf der Oberfläche von Leukozyten und den spezifischen Rezeptoren auf der Oberfläche von epithelialen Zellen ist die Ausbildung eines chemotaktischen Gradienten zur Att¬ raktion der Leukozyten an den Ort der Entzündung von herausragender Bedeutung.The attraction of leukocytes to a specific site of vasculature and subsequent immigration / migration into the underlying damaged tissue are the basis for the development of inflammation. In addition to the expression of various adhesion molecules (selec- tines, ICAM, VCAM) on the surface of leucocytes and the specific receptors on the surface of epithelial cells, the formation of a chemotactic gradient for attracting leukocytes to the site of inflammation is of outstanding importance.
Interleukin-8 (IL-8) gehört zu der Klasse der pro-inflammatorischen Chemokine mit der Fähigkeit zur Attraktion von Leukozyten. Die Rolle von IL-8 in verschiedenen entzündlichen Erkrankungen ist hinlänglich beschrieben. Die biologischen Effekte von IL-8 werden über die Bindung an zwei spezifische Rezeptoren, CXCRl und CXCR2, auf der Zelloberfläche von Zielzellen vermittelt (Baggiolini M., Annu Rev Immunol 1997, 15, 675-705; Baggiolini M., J Int Med 2001, 250, 91- 104).Interleukin-8 (IL-8) belongs to the class of pro-inflammatory chemokines with the ability to attract leukocytes. The role of IL-8 in various inflammatory diseases is well described. The biological effects of IL-8 are mediated via binding to two specific receptors, CXCR1 and CXCR2, on the cell surface of target cells (Baggiolini M, Annu Rev Immunol 1997, 15, 675-705, Baggiolini M, J Int Med 2001 , 250, 91-104).
Die entzündliche Komponente in der Pathophysiologie der Arteriosklerose ist allgemein anerkannt. Diese wird ebenso durch Entzündungszellen (T-Zellen, Monozyten, Makrophagen) und sezernier- te Mediatoren (Zytokine, Chemokine) ausgelöst (Libby P., Nature 2002, 420, 868-874; Boisvert W.A., Trends Cardiovasc Med 2004, 14, 7-18). Die entzündlichen Gefäßveränderungen entstehen durch die Reaktion von einwandernden Monozyten mit pathogenen Lipoproteinen in der Arterien¬ wand. Besonders die Entstehung von sogenannten „Schaumzellen" aus den eingewanderten Mono- zyten durch Aufnahme von oxidierten Lipiden nimmt eine zentrale Rolle hinsichtlich der PIa- queentwicklung und -Stabilität ein. Die Produktion und Wirkung von Chemokinen ist in starkem Maße am Fortgang dieser Plaqueentwicklung beteiligt. Gerade IL-8 ist für die Akkumulation von Lipid-beladenen Makrophagen im atherosklerotischen Gewebe verantwortlich (Boisvert W.A. et al, J Clin luvest 1998, 101, 353-363). Darüber hinaus wird DL-8 und sein spezifischer Rezeptor CXCR2 in atherosklerotischen Läsionen vermehrt exprimiert.The inflammatory component in the pathophysiology of arteriosclerosis is generally recognized. This is also triggered by inflammatory cells (T cells, monocytes, macrophages) and secreted mediators (cytokines, chemokines) (Libby P., Nature 2002, 420, 868-874, Boisvert WA, Trends Cardiovasc Med 2004, 14, 7 -18). The inflammatory vascular changes are caused by the reaction of migrating monocytes with pathogenic lipoproteins in the arterial wall. In particular, the formation of so-called "foam cells" from the migrated monocytes by the uptake of oxidized lipids plays a central role in the development and stability of pi- cadone.The production and effect of chemokines is strongly involved in the progression of this plaque development IL-8 is for the accumulation of Lipid-laden macrophages in atherosclerotic tissue responsible (Boisvert WA et al, J Clin luvest 1998, 101, 353-363). In addition, DL-8 and its specific receptor CXCR2 is increasingly expressed in atherosclerotic lesions.
Ein Antagonist des IL-8 Rezeptors würde die Makrophagen-Anreicherung in den Läsionen stoppen und wäre damit nützlich für die Behandlung von Arteriosklerose.An antagonist of the IL-8 receptor would stop macrophage accumulation in the lesions and would thus be useful for the treatment of arteriosclerosis.
Außerdem könnten IL-8 Rezeptor-Antagonisten bei jeder Krankheit, die aktivierte Monozyten, Makrophagen oder Lymphozyten aufweist, ihre Anwendung finden, da alle diese Zellen den Re¬ zeptor exprimieren.In addition, IL-8 receptor antagonists could find application in any disease involving activated monocytes, macrophages, or lymphocytes, since all of these cells express the receptor.
Eine Aufgabe der vorliegenden Erfindung ist es daher, neue IL-8-Rezeptor Antagonisten zur Be- handlung von inflammatorischen Erkrankungen (besonders Haut-, Atemwegs- und Herz-Kreislauf- Erkrankungen) bei Menschen und Tieren zur Verfügung zu stellen.It is therefore an object of the present invention to provide new IL-8 receptor antagonists for the treatment of inflammatory diseases (especially skin, respiratory and cardiovascular diseases) in humans and animals.
Überraschenderweise wurde gefunden, dass die in der vorliegenden Erfindung beschriebenen [(Phenylethanoyl)amino]benzamide IL-8-Rezeptor Antagonisten sind.Surprisingly, it has been found that the [(phenylethanoyl) amino] benzamides described in the present invention are IL-8 receptor antagonists.
Gegenstand der Erfindung sind Verbindungen der FormelThe invention relates to compounds of the formula
in welcherin which
Y für eine Bindung, Methandiyl, Schwefel oder Sauerstoff steht,Y is a bond, methanediyl, sulfur or oxygen,
R1 für Biphenyl-4-yl steht, wobei in Biphenyl-4-yl 1 bis 3 Kohlenstoffatome durch Stickstoff ersetzt sein können,R 1 is biphenyl-4-yl, where in biphenyl-4-yl 1 to 3 carbon atoms may be replaced by nitrogen,
oderor
für l,3-Benzodioxol-5-yl oder 2,3-Dihydro-l,4-benzodioxin-5-yl steht,is l, 3-benzodioxol-5-yl or 2,3-dihydro-l, 4-benzodioxin-5-yl,
oderor
für eine Gruppe der Formel for a group of the formula
steht,stands,
wobeiin which
X für N, O oder S steht,X is N, O or S,
* die Anknüpfstelle an das Kohlenstoffatom ist, und* is the point of attachment to the carbon atom, and
der Phenylring über die 4 oder 5 Position gebunden ist, wenn der Fünfring über die 2-Position an das Kohlenstoffatom gebunden ist, oder der Phenylring über die 5 Position gebunden ist, wenn der Fünfring über die 3 -Position an das Kohlenstoff¬ atom gebunden ist,the phenyl ring is attached via the 4 or 5 position if the five-membered ring is bonded to the carbon atom via the 2-position, or the phenyl ring is bonded via the 5-position if the five-membered ring is bonded to the carbon atom via the 3-position .
oderor
Naphth-1-yl oder Naphth-2-yl steht, wobei in Naphth-1-yl und Naphth-2-yl 1 Kohlenstoff¬ atom durch Stickstoff ersetzt sein kann,Naphth-1-yl or naphth-2-yl, where in naphth-1-yl and naphth-2-yl 1 carbon atom may be replaced by nitrogen,
oderor
für eine Gruppe der Formelfor a group of the formula
steht,stands,
wobeiin which
W für C oder N steht,W is C or N,
V für N, O oder S steht,V is N, O or S,
* die Anknüpfstelle an das Kohlenstoffatom ist, und die Gruppe über die 2, 3, 5 oder 6 Position an das Kohlenstoffatom gebunden ist,* is the point of attachment to the carbon atom, and the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
oderor
für eine Gruppe der Formelfor a group of the formula
steht,stands,
wobeiin which
U für N, O oder S steht,U stands for N, O or S,
* die Anknüpfstelle an das Kohlenstoffatom ist, und* is the point of attachment to the carbon atom, and
die Gruppe über die 2, 3, 5 oder 6 Position an das Kohlenstoffatom gebunden ist,the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
wobei die Reste R1 substituiert sein können mit 1 bis 3 Substituenten, wobei die Sub- stituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Ci-Cβ-Alkyl, C1-CO- Alkoxy, Ci-Cβ-Alkylamino, Hydroxycarbonyl, Ci-Cδ-Alkoxycarbonyl, Aminocarbonyl, C1- Cδ-Alkylaminocarbonyl, Ci-Cö-Alkylcarbonyl und Ci-Cβ-Alkylcarbonylammo,where the radicals R 1 can be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C O - alkoxy, Ci-Cβ alkylamino, hydroxycarbonyl, Ci-C δ alkoxycarbonyl, aminocarbonyl, C 1 - C δ alkylaminocarbonyl, Ci-C ö alkylcarbonyl and Ci-Cβ-Alkylcarbonylammo,
R2 für Wasserstoff, Cj-C6-Alkyl oder C3-C7-Cycloalkyl steht,R 2 is hydrogen, C 1 -C 6 -alkyl or C 3 -C 7 -cycloalkyl,
R3 für C3-C7-Cycloalkyl oder gegebenenfalls mit bis zu fünf Fluor substituiertes C1-C4-AIl^yI steht,R 3 is C 3 -C 7 -cycloalkyl or optionally substituted by up to five fluorine-substituted C 1 -C 4 -alkyl,
R7 für eine Gruppe der FormelR 7 is a group of the formula
steht,stands,
wobei * die Anknüpfstelle an Y ist,in which * is the link to Y,
R4, R5 und R6 unabhängig voneinander für Wasserstoff, Hydroxy, Amino, Halo¬ gen, Cyano, Trifiuormethyl, Trifluormethoxy, Ci-Cβ-Alkyl, C1-Co-AIkOXy, Ci-Cö-Alkylamino, C3-C7-Cycloalkyl, 5- bis 7-gliedriges Heterocyclyl, Ce- Qo-Aryl, 5- oder 6-gliedriges Heteroaryl, Hydroxycarbonyl, Ci-Ce-R 4, R 5 and R 6 gen independently hydrogen, hydroxy, amino, Halo¬, cyano, Trifiuormethyl, trifluoromethoxy, Ci-Cβ alkyl, C 1 -Co -alkoxy, Ci-C ö alkylamino, C 3 - C 7 -cycloalkyl, 5- to 7-membered heterocyclyl, Ce- Qo-aryl, 5- or 6-membered heteroaryl, hydroxycarbonyl, C 1 -C 6 -cycloalkyl,
Alkoxycarbonyl, Aminocarbonyl, Ci-C6-Alkylaminocarbonyl, Ci-Cβ- Alkylcarbonyl oder Ci-Co-Alkylcarbonylamino steht,Alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl or C 1 -C -alkylcarbonylamino,
worin Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl substituiert sein kön¬ nen mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig vonein- ander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino,in which cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino,
Halogen, Cyano, Trifiuormethyl, Trifluormethoxy, CrC6-Alkyl, CpC6- Alkoxy, Q-Cβ-Alkylamino, Hydroxycarbonyl, Ci-C6-Alkoxycarbonyl, A- minocarbonyl, Ci-Ce-Alkylaminocarbonyl, Ci-C6-Alkylcarbonyl und Ci- Cö-Alkylcarbonylamino,Halogen, cyano, Trifiuormethyl, trifluoromethoxy, C r C 6 alkyl, CpC 6 - alkoxy, Q-Cβ alkylamino, hydroxycarbonyl, Ci-C 6 alkoxycarbonyl, minocarbonyl A-, Ci-Ce-alkylaminocarbonyl, Ci-C 6 - alkylcarbonyl and Ci C ö alkylcarbonylamino,
oderor
R4 und R5 an benachbarte Kohlenstoffatome gebunden sind und eine -0-CH2-CH2-O- Brücke bilden,R 4 and R 5 are attached to adjacent carbon atoms and form a -O-CH 2 -CH 2 -O- bridge,
oderor
für ein 5- oder 6-gliedriges Heteroaryl steht,represents a 5- or 6-membered heteroaryl,
worin Heteroaryl substituiert sein kann mit 1 bis 3 Substituenten, wobei die Substi¬ tuenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifiuormethyl, Trifluormethoxy, Ci-C6-Alkyl, Ci-C6-Alkoxy und Ci-C6-Alkylamino,wherein heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C 6 alkyl, Ci-C 6 alkoxy and C 1 -C 6 -alkylamino,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.and their salts, their solvates, and the solvates of their salts.
Erfindungsgemäße Verbindungen sind die Verbindungen der Formel (Ia) und (I) und deren Salze, Solvate und Solvate der Salze, sowie die von Formel (Ia) und (I) umfassten, nachfolgend als Aus- führungsbeispiel(e) genannten Verbindungen und deren Salze, Solvate und Solvate der Salze, so¬ weit es sich bei den von Formel (Ia) und (I) umfassten, nachfolgend genannten Verbindungen nicht bereits um Salze, Solvate bzw. Solvate der Salze handelt. Die erfϊndungsgemäßen Verbindungen können in Abhängigkeit von ihrer Struktur in stereoisomeren Formen (Enantiomere, Diastereomere) existieren. Die Erfindung betrifft daher die Enantiomeren oder Diastereomeren und ihre jeweiligen Mischungen. Aus solchen Mischungen von Enantiomeren und/oder Diastereomeren lassen sich die stereoisomer einheitlichen Bestandteile in bekannter Weise isolieren.Compounds of the invention are the compounds of the formula (Ia) and (I) and their salts, solvates and solvates of the salts, as well as those of the formula (Ia) and (I), hereinafter referred to as the exemplary embodiment (e) compounds and salts thereof , Solvates and solvates of the salts, as far as the compounds of formula (Ia) and (I) mentioned below are not already salts, solvates or solvates of the salts. Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
Sofern die erfindungsgemäßen Verbindungen in tautomeren Formen vorkommen können, umfasst die vorliegenden Erfindung sämtliche tautomere Formen.If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
Als Salze sind im Rahmen der vorliegenden Erfindung physiologisch unbedenkliche Salze der erfin¬ dungsgemäßen Verbindungen bevorzugt. Umfasst sind aber auch Salze, die für pharmazeutische An- Wendungen selbst nicht geeignet sind aber beispielsweise für die Isolierung oder Reinigung der erfin¬ dungsgemäßen Verbindungen verwendet werden können.Salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to the invention.
Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen umfassen Säure¬ additionssalze von Mineralsäuren, Carbonsäuren und Sulfonsäuren, z.B. Salze der Chlorwasser¬ stoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethansulfon- säure, Toluolsulfonsäure, Benzolsulfonsäure, Naphthalindisulfonsäure, Essigsäure, Trifluoressig- säure, Propionsäure, Milchsäure, Weinsäure, Äpfelsäure, Zitronensäure, Fumarsäure, Maleinsäure und Benzoesäure.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, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen umfassen auch Salze üblicher Basen, wie beispielhaft und vorzugsweise Alkalimetallsalze (z.B. Natrium- und Kalium- salze), Erdalkalisalze (z.B. Calcium- und Magnesiumsalze) und Ammoniumsalze, abgeleitet von Ammoniak oder organischen Aminen mit 1 bis 16 C-Atomen, wie beispielhaft und vorzugsweise Ethylamin, Diethylamin, Triethylamin, Ethyldiisopropylamin, Monoethanolamin, Diethanolamin, Triethanolamin, Dicyclohexylamin, Dimethylaminoethanol, Prokain, Dibenzylamin, N-Methyl- morpholin, Arginin, Lysin, Ethylendiamin und N-Methylpiperidin.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. 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.
Als Solvate werden im Rahmen der Erfindung solche Formen der erfindungsgemäßen Verbindungen bezeichnet, welche in festem oder flüssigem Zustand durch Koordination mit Lösungs¬ mittelmolekülen einen Komplex bilden. Hydrate sind eine spezielle Form der Solvate, bei denen die Koordination mit Wasser erfolgt.In the context of the invention, solvates 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.
Die freie Base der Salze der erfindungsgemäßen Verbindungen kann zum Beispiel durch Zusatz einer wässrigen Base, beispielsweise verdünnte Natronlauge, und anschließende Extraktion mit einem Lösungsmittel nach dem Fachmann bekannten Methoden erhalten werden. Im Rahmen der vorliegenden Erfindung haben die Substituenten, soweit nicht anders spezifiziert, die folgende Bedeutung:The free base of the salts of the compounds according to the invention can be obtained, for example, by addition of an aqueous base, for example dilute sodium hydroxide solution, and subsequent extraction with a solvent by methods known to the person skilled in the art. Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl per se und "Alk" und "Alkyl" in Alkoxy. Alkylamino, Alkoxycarbonyl, Alkylaminocarbonyl. Alkylcarbonyl und Alkylcarbonylamino stehen für einen linearen oder verzweigten Alkylrest mit in der Regel 1 bis 6, vorzugsweise 1 bis 4, besonders bevorzugt 1 bis 3 Kohlenstoffatomen, beispielhaft und vorzugsweise für Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, tert-Butyl, n-Pentyl und n-Hexyl.Alkyl per se and "alk" and "alkyl" in alkoxy. Alkylamino, alkoxycarbonyl, alkylaminocarbonyl. Alkylcarbonyl and Alkylcarbonylamino stand for a linear or branched alkyl radical with usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl Butyl, n-pentyl and n-hexyl.
Alkoxy steht beispielhaft und vorzugsweise für Methoxy, Ethoxy, n-Propoxy, Isopropoxy, tert.- Butoxy, n-Pentoxy und n-Hexoxy.Alkoxy is exemplified and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
Alkylamino steht für einen Alkylaminorest mit einem oder zwei (unabhängig voneinander gewähl- ten) Alkylsubstituenten, beispielhaft und vorzugsweise für Methylamino, Ethylamino, n-Propyl- amino, Isopropylamino, tert.-Butylamino, n-Pentylamino, n-Hexylamino, N,N-Dimethylamino, NN-Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N Dimethylamino, NN
Diethylamino, N-Ethyl-N-methylamino, N-Methyl-N-n-propylamino, N-Isopropyl-N-n-propylamino,Diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino,
N-tert.-Butyl-N-methylamino, N-Ethyl-N-n-pentylamino und N-n-Hexyl-N-methyl-amino. C1-C3-N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methyl-amino. C 1 -C 3 -
Alkylamino steht beispielsweise für einen Monoalkylaminorest mit 1 bis 3 Kohlenstoffatomen oder für einen Dialkylaminorest mit jeweils 1 bis 3 Kohlenstoffatomen pro Alkylsubstituent.Alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.
Alkoxy carbonyl steht beispielhaft und vorzugsweise für Methoxycarbonyl, Ethoxycarbonyl, n-Pro- poxycarbonyl, Isopropoxycarbonyl, tert.-Butoxycarbonyl, n-Pentoxycarbonyl und n-Hexoxycarbonyl.Alkoxycarbonyl is by way of example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
Alkylaminocarbonyl steht für einen Alkylaminocarbonylrest mit einem oder zwei (unabhängig voneinander gewählten) Alkylsubstituenten, wobei die Alkylsubstituenten unabhängig voneinander in der Regel 1 bis 6, bevorzugt 1 bis 4, besonders bevorzugt 1 bis 3 Kohlenstoffatome aufweisen, beispielhaft und vorzugsweise für Methylaminocarbonyl, Ethylaminocarbonyl, n-Propylamino- carbonyl, Isopropylaminocarbonyl, tert-Butylaminocarbonyl, n-Pentylaminocarbonyl, n-Hexyl- aminocarbonyl, N.N-Dimethylaminocarbonyl, N,N-Diethylaminocarbonyl, N-Ethyl-N-methyl- aminocarbonyl, N-Methyl-N-n-propylaminocarbonyl, N-Isopropyl-N-n-propylaminocarbonyl, N-tert.- Butyl-N-methylaminocarbonyl, N-Ethyl-N-n-pentylamino-carbonyl und N-n-Hexyl-N-methylamino- carbonyl. Ci-C3-Alkylaminocarbonyl steht beispielsweise für einen Monoalkylaminocarbonylrest mit 1 bis 3 Kohlenstoffatomen oder für einen Dialkylaminocarbonylrest mit jeweils 1 bis 3 Kohlen¬ stoffatomen pro Alkylsubstituent.Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, the alkyl substituents independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n -Propylaminocarbonyl, isopropylaminocarbonyl, tert -butylaminocarbonyl, n -pentylaminocarbonyl, n -hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N -diethylaminocarbonyl, N -ethyl-N-methylaminocarbonyl, N -methyl-Nn-propylaminocarbonyl, N -Isopropyl-Nn-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl. C 1 -C 3 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
Alkylcarbonyl steht beispielhaft und vorzugsweise für Methylcarbonyl, Ethylcarbonyl, n-Propyl- carbonyl, Isopropylcarbonyl, tert.-Butylcarbonyl, n-Pentylcarbonyl und n-Hexylcarbonyl. Alkylcarbonylamino steht beispielhaft und vorzugsweise für Methylcarbonylamino, Ethylcarbonyl- amino, n-Propylcarbonylamino, Isopropylcarbonylamino, tert.-Butyl-carbonylamino, n-Pentyl- carbonylamino und n-Hexylcarbonylamino.Alkylcarbonyl is by way of example and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl. Alkylcarbonylamino is by way of example and preferably methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
Cycloalkyl steht für eine Cycloalkylgruppe mit in der Regel 3 bis 7, bevorzugt 5 bis 7 Kohlen- stoffatomen, beispielhaft und vorzugsweise für Cycloalkyl sind genannt Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl und Cycloheptyl.Cycloalkyl is a cycloalkyl group having usually 3 to 7, preferably 5 to 7 carbon atoms, by way of example and preferably cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Aryl steht für einen mono- oder bicyclischen aromatischen Rest mit in der Regel 6 bis 10 Kohlen¬ stoffatomen, beispielhaft und vorzugsweise für Aryl sind genannt Phenyl und Naphthyl.Aryl is a mono- or bicyclic aromatic radical having generally 6 to 10 carbon atoms, by way of example and preferably aryl are phenyl and naphthyl.
Heteroaryl steht für einen aromatischen, monocyclischen Rest mit in der Regel 5 oder 6 Ringato- men und bis zu 4, vorzugsweise bis zu 2 Heteroatomen aus der Reihe S, O und N, wobei ein Stick¬ stoffatom auch ein N-Oxid bilden kann, beispielhaft und vorzugsweise für Thienyl, Furyl, Pyrrolyl, Thiazolyl, Oxazolyl, Oxadiazolyl, Pyrazolyl, Imidazolyl, Pyridyl, Pyrimidyl, Pyridazinyl, Pyrazinyl.Heteroaryl is an aromatic, monocyclic radical having usually 5 or 6 ring atoms and up to 4, preferably up to 2 heteroatoms from the series S, O and N, where a nitrogen atom can also form an N-oxide, by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.
Heterocyclyl steht für einen monocyclischen, heterocyclischen Rest mit in der Regel 5 bis 7 Ring¬ atomen und bis zu 3, vorzugsweise bis zu 2 Heteroatomen und/oder Heterogruppen aus der Reihe N, O, S, SO, SO2, wobei ein Stickstoffatom auch ein N-Oxid bilden kann. Die Heterocyclyl-Reste können gesättigt oder teilweise ungesättigt sein. Bevorzugt sind 5- bis 7-gliedrige, monocyclische gesättigte Heterocyclylreste mit bis zu zwei Heteroatomen aus der Reihe O, N und S, beispielhaft und vorzugsweise für Pyrrolidin-2-yl, Pyrrolidin-3-yl, Pyrrolinyl, Tetrahydrofuranyl, Tetra- hydrothienyl, Pyranyl, Piperidin-1-yl, Piperidin-2-yl, Piperidin-3-yl, Piperidin-4-yl, Thiopyranyl, Morpholin-1-yl, Morpholin-2-yl, Morpholin-3-yl, Perhydroazepinyl, Piperazin-1-yl, Piperazin-2-yl.Heterocyclyl is a monocyclic, heterocyclic radical having usually 5 to 7 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO 2 , where a nitrogen atom also can form an N-oxide. The heterocyclyl radicals may be saturated or partially unsaturated. Preference is given to 5- to 7-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S, by way of example and preferably for pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, Pyranyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, perhydroazepinyl, piperazine 1-yl, piperazin-2-yl.
Halogen steht für Fluor, Chlor, Brom und Jod, vorzugsweise für Fluor und Chlor.Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
Wenn Reste in den erfindungsgemäßen Verbindungen substituiert sind, können die Reste, soweit nicht anders spezifiziert, ein- oder mehrfach gleich oder verschieden substituiert sein. Eine Sub¬ stitution mit bis zu drei gleichen oder verschiedenen Substituenten ist bevorzugt. Ganz besonders bevorzugt ist die Substitution mit einem Substituenten.If radicals are substituted in the compounds according to the invention, the radicals may, unless otherwise specified, be mono- or polysubstituted or differently substituted. A substitution with up to three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
Bevorzugt sind solche Verbindungen der Formel (Ia), die der Formel Preferred compounds of the formula (Ia) are those of the formula
entsprechen, in welchercorrespond, in which
Y für eine Bindung oder Methandiyl steht,Y is a bond or methanediyl,
R1 für Biphenyl-4-yl steht, wobei in Biphenyl-4-yl 1 bis 3 Kohlenstoffatome durch Stickstoff ersetzt sein können,R 1 is biphenyl-4-yl, where in biphenyl-4-yl 1 to 3 carbon atoms may be replaced by nitrogen,
oderor
für l,3-Benzodioxol-5-yl oder 2,3-Dihydro-l,4-benzodioxin-5-yl steht,is l, 3-benzodioxol-5-yl or 2,3-dihydro-l, 4-benzodioxin-5-yl,
oderor
für eine Gruppe der Formelfor a group of the formula
steht,stands,
wobeiin which
X für N, O oder S steht,X is N, O or S,
* die Anknüpfstelle an das Kohlenstoffatom ist, und* is the point of attachment to the carbon atom, and
der Phenylring über die 4 oder 5 Position gebunden ist, wenn der Fünfring über die 2-Position an das Kohlenstoffatom gebunden ist, oder der Phenylring über die 5 Position gebunden ist, wenn der Fünfring über die 3-Position an das Kohlenstoff¬ atom gebunden ist,the phenyl ring is attached through the 4 or 5 position when the five-membered ring is attached to the carbon atom through the 2-position, or the phenyl ring is attached through the 5-position Position is bound when the five-membered ring is bonded to the carbon atom via the 3-position,
oderor
Naphth-1-yl oder Naphth-2-yl steht, wobei in Naphth-1-yl und Naphth-2-yl 1 Kohlenstoff¬ atom durch Stickstoff ersetzt sein kann,Naphth-1-yl or naphth-2-yl, where in naphth-1-yl and naphth-2-yl 1 carbon atom may be replaced by nitrogen,
oderor
für eine Gruppe der Formelfor a group of the formula
steht,stands,
wobeiin which
W für C oder N steht,W is C or N,
V für N, O oder S steht,V is N, O or S,
* die Anknüpfstelle an das Kohlenstoffatom ist, und* is the point of attachment to the carbon atom, and
die Gruppe über die 2, 3, 5 oder 6 Position an das Kohlenstoffatom gebunden ist,the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
oderor
für eine Gruppe der Formelfor a group of the formula
steht,stands,
wobeiin which
U für N, O oder S steht, * die Anknüpfstelle an das Kohlenstoffatom ist, undU stands for N, O or S, * is the point of attachment to the carbon atom, and
die Gruppe über die 2, 3, 5 oder 6 Position an das Kohlenstoffatom gebunden ist,the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
wobei die Reste R1 substituiert sein können mit 1 bis 3 Substituenten, wobei die Sub- stituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Ci-Cö-Alkyl, Q-Ce-where the radicals R 1 may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C ö alkyl, Q-Ce -
Alkoxy, Ci-Cö-Alkylamino, Hydroxycarbonyl, Ci-Cβ-Alkoxycarbonyl, Aminocarbonyl, C]- C6-Alkylammocarbonyl, Ci-Cö-Alkylcarbonyl und Q-Cö-Alkylcarbonylamino,Alkoxy, Ci-C ö alkylamino, hydroxycarbonyl, Ci-Cβ-alkoxycarbonyl, aminocarbonyl, C] - C 6 -Alkylammocarbonyl, Ci-C ö ö alkylcarbonyl and QC alkylcarbonylamino,
R2 für Wasserstoff, Ci-C6-Alkyl oder C3-C7-Cycloalkyl steht,R 2 is hydrogen, C 1 -C 6 -alkyl or C 3 -C 7 -cycloalkyl,
R3 für C3-C7-Cy cloalkyl oder gegebenenfalls mit bis zu fünf Fluor substituiertes Ci-Gj-Alkyl steht,R 3 is C 3 -C 7 -cycloalkyl or optionally substituted by up to five fluorine-substituted Ci-Gj-alkyl,
R4, R5 und R6 unabhängig voneinander für Wasserstoff, Hydroxy, Amino, Halogen, Cyano,R 4 , R 5 and R 6 independently of one another represent hydrogen, hydroxyl, amino, halogen, cyano,
Trifluormethyl, Trifluormethoxy, Ci-C6-Alkyl, CrC6-Alkoxy, Ci-C6-Alkylamino, C3-C7-Trifluoromethyl, trifluoromethoxy, Ci-C 6 alkyl, C r C 6 alkoxy, Ci-C 6 -alkylamino, C 3 -C 7 -
Cycloalkyl, 5- bis 7-gliedriges Heterocyclyl, Cβ-Cio-Aryl, 5- oder 6-gliedriges Heteroaryl,Cycloalkyl, 5- to 7-membered heterocyclyl, Cβ-Cio-aryl, 5- or 6-membered heteroaryl,
Hydroxycarbonyl, Ci-Cö-Alkoxycarbonyl, Aminocarbonyl, Ci-Cβ-Alkylaminocarbonyl, Ci-Cö-Alkylcarbonyl oder Ci-Cβ-Alkylcarbonylamino steht,Hydroxycarbonyl, Ci-C ö alkoxycarbonyl, aminocarbonyl, Ci-Cβ-alkylaminocarbonyl, Ci-C ö alkylcarbonyl or Ci-Cβ-Alkylcarbonylamino represents,
worin Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluor¬ methoxy, Ci-Cβ-Alkyl, Ci-Cö-Alkoxy, Ci-C6-Alkylamino, Hydroxycarbonyl, Ci-Cβ- Alkoxycarbonyl, Aminocarbonyl, Ci-Cό-Alkylaminocarbonyl, Cj-Ce-Alkylcarbonyl undwherein cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, Trifluor¬ methoxy, Ci-Cβ-alkyl, Ci -C ö alkoxy, Ci-C 6 -alkylamino, hydroxycarbonyl, Ci-Cβ- alkoxycarbonyl, aminocarbonyl, Ci-C ό alkylaminocarbonyl, Cj-Ce-alkylcarbonyl, and
Ci-Cö-Alkylcarbonylamino,Ci-C ö alkylcarbonylamino,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.and their salts, their solvates, and the solvates of their salts.
Bevorzugt sind auch solche Verbindungen der Formel (I), in welcherPreference is also given to those compounds of the formula (I) in which
Y für eine Bindung oder Methandiyl steht,Y is a bond or methanediyl,
R1 für Biphenyl-4-yl, l,3-Benzodioxol-5-yl, 2,3-Dihydro-l,4-benzodioxin-5-yl, 5-Phenyl- thien-2-yl, 5-Phenyl-furan-2-yl, Naphth-1-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2- yl, l-Benzothien-3-yl, l-Benzothien-5-yl, l-Benzothien-6-yl, l-Benzofuran-2-yl oder l-Benzofuran-3-yl steht, wobei Biphenyl-4-yl, l,3-Benzodioxol-5-yl, 2,3-Dihydro-l,4-benzodioxin-5-yl, 5-Phenyl- thien-2-yl, 5-Phenyl-furan-2-yl, Naphth-1-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2- yl, l-Benzothien-3-yl, l-Benzothien-5-yl, l-Benzothien-6-yl, l-Benzofuran-2-yl und l-Benzofiιran-3-yl substituiert sein können mit 1 bis 3 Substituenten, wobei die Sub- stituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend ausR 1 is biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenylthien-2-yl, 5-phenyl-furan -2-yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1-benzothiene 6-yl, 1-benzofuran-2-yl or 1-benzofuran-3-yl, wherein biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenylthien-2-yl, 5-phenyl-furan-2 -yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1-benzothien-6 -yl, 1-benzofuran-2-yl and 1-benzofiιran-3-yl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of
Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Ci-Cό-Alkyl, C1-Ce- Alkoxy, Ci-Cö-Alkylamino, Hydroxycarbonyl, Ci-Cβ-Alkoxycarbonyl, Aminocarbonyl, Ci-Cβ-Alkylaminocarbonyl, Ci-Cö-Alkylcarbonyl und Ci-Cö-Alkylcarbonylamino,Hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C ό -alkyl, C 1 -Ce- alkoxy, Ci-C ö alkylamino, hydroxycarbonyl, Ci-Cβ-alkoxycarbonyl, aminocarbonyl, Ci-Cβ-alkylaminocarbonyl, Ci -C ö alkylcarbonyl and Ci-C ö alkylcarbonylamino,
R2 für Wasserstoff oder CrC6-Alkyl steht,R 2 is 6 alkyl, hydrogen or C r C,
R3 für C3-C7-Cycloalkyl oder gegebenenfalls mit bis zu fünf Fluor substituiertes C1-C4-AIlCyI steht,R 3 is C 3 -C 7 -cycloalkyl or optionally C 1 -C 4 -alkyl substituted with up to five fluorine,
R4, R5 und R6 unabhängig voneinander für Wasserstoff, Hydroxy, Amino, Halogen, Cyano,R 4 , R 5 and R 6 independently of one another represent hydrogen, hydroxyl, amino, halogen, cyano,
Trifluormethyl, Trifluormethoxy, Ci-C6-Alkyl, CrC6-Alkoxy, CrC6-Alkylamino, C3-C7-Trifluoromethyl, trifluoromethoxy, Ci-C 6 alkyl, C r C 6 alkoxy, C r C 6 alkylamino, C 3 -C 7 -
Cycloalkyl, 5- bis 7-gliedriges Heterocyclyl, Cβ-Cio-Aryl, 5- oder 6-gliedriges Heteroaryl, Hydroxycarbonyl, C]-C6-Alkoxycarbonyl, Aminocarbonyl, Ci-Cβ-Alkylaminocarbonyl, Q-Cycloalkyl, 5- to 7-membered heterocyclyl, Cβ-Cio-aryl, 5- or 6-membered heteroaryl, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, Q-
Cβ-Alkylcarbonyl oder Ci-Cö-Alkylcarbonylamino steht,Cβ-alkylcarbonyl or Ci-C ö alkylcarbonylamino,
worin Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluor- methoxy, Ci-C6-Alkyl, C1-C6-AIkOXy, Ci-C6-Alkylamino, Hydroxycarbonyl, CrC6-in which cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of hydroxyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, Ci-C 6 -alkylamino, hydroxycarbonyl, C r C 6 -
Alkoxycarbonyl, Aminocarbonyl, Ci-Cβ-Alkylaminocarbonyl, Ci-Cβ-Alkylcarbonyl und C i -C6-Alky lcarbonylamino,Alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl and C 1 -C 6 -alkylcarbonylamino,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.and their salts, their solvates, and the solvates of their salts.
Bevorzugt sind auch solche Verbindungen der Formel (I), in welcherPreference is also given to those compounds of the formula (I) in which
Y für eine Bindung oder Methandiyl steht,Y is a bond or methanediyl,
R1 für Biphenyl-4-yl, l,3-Benzodioxol-5-yl, 2,3-Dihydro-l,4-benzodioxin-5-yl, 5-Phenyl- thien-2-yl, 5-Phenyl-furan-2-yl, Naphth-1-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2- yl, l-Benzothien-3-yl, l-Benzothien-5-yl, l-Benzothien-6-yl, l-Benzofuran-2-yl oder l-Benzofuran-3-yl steht, wobei Biphenyl-4-yl, l,3-Benzodioxol-5-yl, 2,3-Dihydro-l,4-benzodioxin-5-yl, 5-Phenyl- thien-2-yl, 5-Phenyl-furan-2-yl, Naphth-1-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2- yl, l-Benzothien-3-yl, l-Benzothien-5-yl, l-Benzothien-6-yl, l-Benzofuran-2-yl und l-Benzofuran-3-yl substituiert sein können mit 1 bis 3 Substituenten, wobei die Sub- stituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend ausR 1 is biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenylthien-2-yl, 5-phenyl-furan -2-yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1-benzothiene 6-yl, 1-benzofuran-2-yl or 1-benzofuran-3-yl, wherein biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenylthien-2-yl, 5-phenyl-furan-2 -yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1-benzothien-6 -yl, 1-benzofuran-2-yl and 1-benzofuran-3-yl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of
Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Ci-Cβ-Alkyl, Ci-Cβ- Alkoxy, Ci-Cö-Alkylamino, Hydroxycarbonyl, Ci-Cβ-Alkoxycarbonyl, Aminocarbonyl, Ci-Cö-Alkylaminocarbonyl, Ci-Cβ-Alkylcarbonyl und Q-Cg-Alkylcarbonylamino,Hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-Cβ alkyl, Ci-Cβ- alkoxy, Ci-C ö alkylamino, hydroxycarbonyl, Ci-Cβ-alkoxycarbonyl, aminocarbonyl, Ci-C ö alkylaminocarbonyl, Ci- Cβ-alkylcarbonyl and Q-Cg-alkylcarbonylamino,
R2 für Wasserstoff oder CrC6-Alkyl steht,R 2 is 6 alkyl, hydrogen or C r C,
R3 für C3-C7-Cycloalkyl oder gegebenenfalls mit bis zu fünf Fluor substituiertes CrQ-Alkyl steht,R 3 is C 3 -C 7 -cycloalkyl or optionally substituted by up to five fluorine-substituted CrQ-alkyl,
R4, R5 und R6 unabhängig voneinander für Wasserstoff, Halogen, Cyano, Trifluormethyl, Tri¬ fluormethoxy, Ci-C6-Alkyl, C3-C7-Cycloalkyl, Hydroxycarbonyl, Ci-Cö-Alkoxycarbonyl, Aminocarbonyl, Ci-Cä-Alkylaminocarbonyl, Ci-Cβ-Alkylcarbonyl oder Ci-Cö-Alkylcarb- onylamino steht,R 4, R 5 and R 6 fluoromethoxy independently hydrogen, halogen, cyano, trifluoromethyl, Tri¬, Ci-C 6 alkyl, C 3 -C 7 -cycloalkyl, hydroxycarbonyl, Ci-C ö alkoxycarbonyl, aminocarbonyl, Ci -C ä alkylaminocarbonyl, Ci-Cβ-alkylcarbonyl or Ci-C ö -Alkylcarb- carbonylamino group,
worin Cycloalkyl substituiert sein kann mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Ami¬ no, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Q-Cβ-Alkyl, Ci-Cβ-Alkoxy, Ci-Cβ- Alkylamino, Hydroxycarbonyl, Ci-Cβ-Alkoxycarbonyl, Aminocarbonyl, CrCβ-Alkyl- aminocarbonyl, Ci-Cβ-Alkylcarbonyl und Ci-Cg-Alkylcarbonylamino,wherein cycloalkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Q-Cβ-alkyl, Ci-Cβ-alkoxy, Ci -Cβ-alkylamino, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl and C 1 -C 6 -alkylcarbonylamino,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.and their salts, their solvates, and the solvates of their salts.
Bevorzugt sind auch solche Verbindungen der Formel (I), in welcherPreference is also given to those compounds of the formula (I) in which
Y für eine Bindung oder Methandiyl steht,Y is a bond or methanediyl,
R1 für Biphenyl-4-yl, 5-Phenyl-thien-2-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2-yl oder l-Benzofuran-2-yl,R 1 is biphenyl-4-yl, 5-phenylthien-2-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl or 1-benzofuran-2-yl,
wobei Biphenyl-4-yl und Naphth-2-yl substituiert sein können mit 1 bis 2 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe be¬ stehend aus Fluor, Chlor, Methoxy und Ethoxy,where biphenyl-4-yl and naphth-2-yl may be substituted by 1 to 2 substituents, where the substituents are selected independently of one another from the group consisting of fluorine, chlorine, methoxy and ethoxy,
R2 für Wasserstoff steht, R3 für Methyl, Ethyl oder Isopropyl steht,R 2 is hydrogen, R 3 is methyl, ethyl or isopropyl,
R4, R5 und R6 unabhängig voneinander für Wasserstoff oder Halogen stehen,R 4 , R 5 and R 6 independently of one another represent hydrogen or halogen,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.and their salts, their solvates, and the solvates of their salts.
Bevorzugt sind auch solche Verbindungen der Formel (I) oder (Ia), in welcher Y für eine Bindung oder Methandiyl steht.Preference is also given to those compounds of the formula (I) or (Ia) in which Y is a bond or methanediyl.
Bevorzugt sind auch solche Verbindungen der Formel (I) oder (Ia), in welcher R1 für Biphenyl-4- yl, 5-Phenyl-thien-2-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2-yl oder l-Benzofuran-2-yl, wobei Biphenyl-4-yl und Naphth-2-yl substituiert sein können mit 1 bis 2 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Fluor, Chlor, Methoxy und Ethoxy.Preference is also given to those compounds of the formula (I) or (Ia) in which R 1 is biphenyl-4-yl, 5-phenylthien-2-yl, naphth-2-yl, quinolin-6-yl, Benzothien-2-yl or l-benzofuran-2-yl, wherein biphenyl-4-yl and naphth-2-yl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of fluorine, chlorine , Methoxy and ethoxy.
Bevorzugt sind auch solche Verbindungen der Formel (I) oder (Ia), in welcher R2 für Wasserstoff steht.Preference is also given to those compounds of the formula (I) or (Ia) in which R 2 is hydrogen.
Bevorzugt sind auch solche Verbindungen der Formel (I) oder (Ia), in welcher R3 für Methyl, Ethyl oder Isopropyl steht.Preference is also given to those compounds of the formula (I) or (Ia) in which R 3 is methyl, ethyl or isopropyl.
Bevorzugt sind auch solche Verbindungen der Formel (I), in welcher R4, R5 und R6 unabhängig voneinander für Wasserstoff oder Halogen stehen.Also preferred are those compounds of formula (I) in which R 4 , R 5 and R 6 are independently hydrogen or halogen.
Bevorzugt sind auch solche Verbindungen der Formel (Ia), in welcher R7 für Triazolyl, Thiazolyl, Pyridyl, Thienyl oder Furyl steht.Preference is also given to those compounds of the formula (Ia) in which R 7 is triazolyl, thiazolyl, pyridyl, thienyl or furyl.
Gegenstand der Erfindung ist weiterhin ein Verfahren zur Herstellung der Verbindungen der For- mel (Ia), wobeiThe invention further provides a process for the preparation of the compounds of formula (Ia), wherein
[A] Verbindungen der Formel[A] Compounds of the formula
in welcher Y, R2, R3 und R7 die oben angegebene Bedeutung haben,in which Y, R 2 , R 3 and R 7 have the abovementioned meaning,
mit Verbindungen der Formelwith compounds of the formula
R 1/ B(OH)2 R 1 / B (OH) 2
(Hi),(Hi),
in welcherin which
R1 die oben angegebene Bedeutung hat,R 1 has the meaning given above,
oderor
[B] Verbindungen der Formel[B] Compounds of the formula
in welcherin which
R1 und R2 die oben angegebene Bedeutung haben,R 1 and R 2 have the abovementioned meaning,
mit Verbindungen der Formelwith compounds of the formula
in welcherin which
Y, R3 und R7 die oben angegebene Bedeutung haben, undY, R 3 and R 7 have the abovementioned meaning, and
X1 für Halogen, bevorzugt Iod oder Brom, oder Hydroxy steht,X 1 is halogen, preferably iodine or bromine, or hydroxy,
umgesetzt werden.be implemented.
Die Umsetzung nach Verfahren [A] erfolgt im Allgemeinen unter Suzuki-Reaktionsbedingungen in inerten Lösungsmitteln, in Gegenwart eines Katalysators, gegebenenfalls in Gegenwart eines Zu¬ satzreagenzes, bevorzugt in einem Temperaturbereich von Raumtemperatur bis 1300C bei Normal- druck (S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58 (48), 9633-9695 und N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483).The reaction according to method [A] is generally carried out under Suzuki reaction conditions in inert solvents in the presence of a catalyst, optionally in the presence of a satzreagenzes Zu¬, preferably in a temperature range from room temperature to 130 0 C at normal Kotha, K., Lahiri, D. Kashinath, Tetrahedron 2002, 58 (48), 9633-9695 and N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483).
Katalysatoren sind beispielsweise für Suzuki-Reaktionsbedingungen übliche Palladium- Katalysatoren, bevorzugt sind Katalysatoren wie z.B. Dichlorbis(triphenylphosphin)palladium, Tetrakistriphenylphosphmpalladium(O), Palladium(II)acetat, l,r-Bis[(diphenylphosphino)-ferro- cen]palladium-II-chlorid (l:l)-Komplex mit Dichlormethan.For example, catalysts are conventional palladium catalysts for Suzuki reaction conditions, preferably catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphmpalladium (O), palladium (II) acetate, l, r-bis [(diphenylphosphino) ferrocen] palladium II chloride (1: 1) complex with dichloromethane.
Zusatzreagenzien sind beispielsweise Kaliumacetat, Cäsium-, Kalium- oder Natriumcarbonat, Ba¬ riumhydroxid, Kalium-tert.-butylat, Cäsiumfluorid oder Kaliumphosphat durchgeführt, bevorzugt sind Zusatzreagenzien wie z.B. Kaliumacetat und/oder wässrige Natriumcarbonatlösung.Additional reagents are for example potassium acetate, cesium, potassium or sodium carbonate, Ba¬ riumhydroxid, potassium tert-butoxide, cesium fluoride or potassium phosphate carried out, preference is given to additional reagents such. Potassium acetate and / or aqueous sodium carbonate solution.
Inerte Lösungsmittel sind beispielsweise Ether wie Dioxan, Tetrahydrofuran oder 1,2-Dimeth- oxyethan, Kohlenwasserstoffe wie Benzol, Xylol oder Toluol, oder andere Lösemittel wie Nitro- benzol, Dimethylformamid, Dimethylacetamid, Dimethylsulfoxid oder N-Methylpyrrolidon, be¬ vorzugt sind Lösungsmittel wie z.B. Dimethylformamid, Dimethylacetamid, Dimethylsulfoxid oder 1,2-Dimethoxyethan.Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or other solvents, such as nitrobenzene, dimethylformamide, dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone. Preferred solvents are eg Dimethylformamide, dimethylacetamide, dimethylsulfoxide or 1,2-dimethoxyethane.
Die Umsetzung nach Verfahren [B] erfolgt, falls X1 gleich Halogen ist, im Allgemeinen in inerten Lösungsmitteln, in Gegenwart einer Base, bevorzugt in einem Temperaturbereich von O0C bis 4O0C bei Normaldruck.The reaction according to process [B] is carried out, if X 1 is halogen, generally in inert solvents, in the presence of a base, preferably in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
Inerte Lösungsmittel sind beispielsweise Halogenkohlenwasserstoffe wie Methylenchlorid, Tri- chlormethan oder 1,2-Dichlorethan, Ether wie Dioxan, Tetrahydrofuran oder 1,2-Dimethoxyethan, oder andere Lösemittel wie Aceton, Dimethylformamid, Dimethylacetamid, 2-Butanon oder Ace- tonitril, bevorzugt ist Tetrahydrofuran oder Methylenchlorid.Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, is preferred Tetrahydrofuran or methylene chloride.
Basen sind beispielsweise Alkalicarbonate wie Cäsiumcarbonat, Natrium- oder Kaliumcarbonat, oder Natrium- oder Kaliummethanolat, oder Natrium- oder Kaliumethanolat oder Kalium-tert.- butylat, oder Amide wie Natriumamid, Lithium-bis-(trimethylsilyl)amid oder Lithiumdiisopropyl- amid, oder andere Basen wie Natriumhydrid, DBU, Triethylamin oder Diisopropylethylamin, be¬ vorzugt ist Diisopropylethylamin.Examples of bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, be¬ preferred is diisopropylethylamine.
Die Umsetzung nach Verfahren [B] erfolgt, falls X1 gleich Hydroxy ist, im Allgemeinen in inerten Lösungsmitteln, in Gegenwart von Dehydratisierungsreagenzien, gegebenenfalls in Gegenwart einer Base, bevorzugt in einem Temperaturbereich von O0C bis Raumtemperatur bei Normaldruck.The reaction according to process [B] is carried out, if X 1 is hydroxy, generally in inert solvents, in the presence of dehydrating reagents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to room temperature at normal pressure.
Als Dehydratisierungsreagenzien eignen sich hierbei beispielsweise Carbodiimide wie z.B. N,N'- Diethyl-, NN'-Dipropyl-, NN'-Diisopropyl-, NN'-Dicyclohexylcarbodiimid, N-(3-Dimethylamino- isopropyl)-N'-ethylcarbodiimid-Hydrochlorid (EDC) (gegebenenfalls in Gegenwart von Penta- fluorphenol (PFP)), N-Cyclohexylcarbodiimid-N'-propyloxymethyl-Polystyrol (PS-Carbodiimid) oder Carbonylverbindungen wie Carbonyldiimidazol, oder 1,2-Oxazoliumverbindungen wie 2-Ethyl-5-phenyl-l,2-oxazolium-3-sulfat oder 2-tert.-Butyl-5-methyl-isoxazolium-perchlorat, oder Acylaminoverbindungen wie 2-Ethoxy-l-ethoxycarbonyl-l,2-dihydrochinolin, oder Propanphos- phonsäureanhydrid, oder Isobutylchloroformat, oder Bis-(2-oxo-3-oxazolidinyl)-phosphorylchlorid oder Benzotriazolyloxy-tri(dimethylamino)phosphoniumhexafluorophosphat, oder 0-(Benzotria- zol-l-yl)-N,NN',N'-tetra-methyluronium-hexafluorophosphat (HBTU), 2-(2-Oxo-l-(2H)-pyridyl)- 1,1,3,3-tetramethyluroniumtetrafluoroborat (TPTU) oder O-(7-Azabenzotriazol-l-yl)-N,N,N',N- tetramethyl-uroniumhexafluorophosphat (HATU), oder 1-Hydroxybenztriazol (HOBt), oder Ben- zotriazol-l-yloxytris(dimethylamino)-phosphoniumhexafluorophosphat (BOP), oder Mischungen aus diesen, mit Basen. Vorzugsweise wird die Kondensation mit HOBt und EDC durchgeführt.Examples of suitable dehydrating reagents are carbodiimides, such as N, N'-diethyl, NN'-dipropyl, NN'-diisopropyl, NN'-dicyclohexylcarbodiimide, N- (3-dimethylamino) isopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2- Oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-l, 2 dihydroquinoline, or propanophosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 0- (benzotriazole-1-yl) -N, NN ' , N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazole-1 -yl) -N, N, N ', N-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or Mischu out of these, with bases. Preferably, the condensation is carried out with HOBt and EDC.
Basen sind beispielsweise Alkalicarbonate, wie z.B. Natrium- oder Kaliumcarbonat, oder -hy- drogencarbonat, oder organische Basen wie Trialkylamine, z.B. Triethylamin, N-Methylmorpholin, N-Methylpiperidin, 4-Dimethylaminopyridin oder Diisopropylethylamin. Vorzugsweise wird die Kondensation mit Diisopropylethylamin durchgeführt.Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine. Preferably, the condensation is carried out with diisopropylethylamine.
Inerte Lösungsmittel sind beispielsweise Halogenkohlenwasserstoffe wie Dichlormethan oder Tri- chlormethan, Kohlenwasserstoff, wie Benzol, Νitromethan, Dioxan, Dimethylformamid, Aceto- nitril oder Hexamethylphosphorsäuretriamid. Ebenso ist es möglich, Gemische der Lösemittel einzusetzen. Besonders bevorzugt ist Dichlormethan oder Dimethylformamid.Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, etromonethane, dioxane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
Die Verbindungen der Formeln (IH) und (V) sind bekannt oder lassen sich nach bekannten Verfah¬ ren aus den entsprechenden Edukten synthetisieren.The compounds of the formulas (IH) and (V) are known or can be synthesized by known processes from the corresponding starting materials.
Die Verbindungen der Formel (ET) sind bekannt oder können hergestellt werden, indem Ver¬ bindungen der FormelThe compounds of the formula (ET) are known or can be prepared by adding compounds of the formula
in welcherin which
R2 die oben angegebene Bedeutung hat, mit Verbindungen der Formel (V) nach Verfahren [B] umgesetzt werden.R 2 has the meaning given above, with compounds of formula (V) according to method [B].
Die Verbindungen der Formel (VI) sind bekannt oder können hergestellt werden, indem die Ver¬ bindung der FormelThe compounds of the formula (VI) are known or can be prepared by the Ver¬ binding of the formula
mit Verbindungen der Formelwith compounds of the formula
X2 X 2
R ^ (vπi),R ^ (vπi),
in welcherin which
R2 die oben angegebene Bedeutung hat, undR 2 has the meaning given above, and
X2 für Halogen, bevorzugt Iod oder Brom, steht,X 2 is halogen, preferably iodine or bromine,
umgesetzt werden.be implemented.
Die Umsetzung erfolgt im Allgemeinen in inerten Lösungsmitteln, gegebenenfalls in Gegenwart einer Base, gegebenenfalls in Gegenwart von Kaliumiodid, bevorzugt in einem Temperaturbereich von Raumtemperatur bis zum Rückfluss der Lösungsmittel bei Normaldruck.The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, if appropriate in the presence of potassium iodide, preferably in a temperature range from room temperature to reflux of the solvents under atmospheric pressure.
Inerte Lösungsmittel sind beispielsweise Halogenkohlenwasserstoffe wie Methylenchlorid, Trich- lormethan oder 1,2-Dichlorethan, Ether wie Dioxan, Tetrahydrofuran oder 1,2-Dimethoxyethan, oder andere Lösemittel wie Aceton, Dimethylformamid, Dimethylacetamid, 2-Butanon oder Ace- tonitril, bevorzugt Tetrahydrofuran, Methylenchlorid, Aceton, 2-Butanon, Acetonitril, Dimethyl¬ formamid oder 1,2-Dimethoxyethan.Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran , Methylene chloride, acetone, 2-butanone, acetonitrile, dimethylformamide or 1,2-dimethoxyethane.
Basen sind beispielsweise Alkalicarbonate wie Cäsiumcarbonat, Natrium- oder Kaliumcarbonat, oder Natrium- oder Kaliummethanolat, oder Natrium- oder Kaliumethanolat oder Kalium-tert.- butylat, oder Amide wie Natriumamid, Lithium-bis-(trimethylsilyl)amid oder Lithiumdiisopropy- lamid, oder metallorganische Verbindungen wie Butyllithium oder Phenyllithium, oder andere Basen wie Natriumhydrid, DBU, bevorzugt Kalium-tert-butylat, Cäsiumcarbonat, DBU, Natrium¬ hydrid, Kaliumcarbonat oder Natriumcarbonat. In einem alternativen Verfahren können die Verbindungen der Formel (VI) hergestellt werden, indem die Verbindung der Formel (VII) mit Verbindungen der FormelExamples of bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride, DBU, preferably potassium tert-butoxide, cesium carbonate, DBU, sodium hydride, potassium carbonate or sodium carbonate. In an alternative method, the compounds of formula (VI) can be prepared by reacting the compound of formula (VII) with compounds of formula
in welcherin which
R2 die oben angegebene Bedeutung hat,R 2 has the meaning given above,
unter Bedingungen der reduktiven Aminierung umgesetzt werden.be reacted under conditions of reductive amination.
Die Umsetzung erfolgt im Allgemeinen in inerten Lösungsmitteln, in Gegenwart eines Redukti¬ onsmittels, bevorzugt in einem Temperaturbereich von -200C bis zum Rückfluss der Lösungsmit¬ tel bei Normaldruck.The reaction is generally carried out in inert solvents, in the presence of a Redukti¬ onsmittels, preferably in a temperature range from -20 0 C to reflux of the Lösungsmit¬ tel at atmospheric pressure.
Inerte Lösungsmittel sind beispielsweise Halogenkohlenwasserstoffe wie Methylenchlorid, Trich- lormethan oder 1,2-Dichlorethan, Alkohole wie Methanol, Ethanol, n-Propanol, iso-Propanol, n- Butanol oder tert-Butanol, oder eine Mischung aus Alkohol und Wasser, bevorzugt ist eine Mi¬ schung aus Methanol und Wasser.Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or a mixture of alcohol and water, is preferred a mixture of methanol and water.
Reduktionsmittel sind beispielsweise Natriumborhydrid oder Triacetoxyborhydrid.Reducing agents are, for example, sodium borohydride or triacetoxyborohydride.
Die Verbindungen der Formel (IV) sind bekannt oder können hergestellt werden, indem die Ver¬ bindung der Formel (VI) mit Verbindungen der Formel (HI) nach Verfahren [A] umgesetzt wer¬ den.The compounds of the formula (IV) are known or can be prepared by reacting the compound of the formula (VI) with compounds of the formula (III) according to process [A].
Die Amidfunktion der Verbindungen der Formeln (H)3 (IV), (VI) und (VH) ist gegebenenfalls wäh¬ rend der Umsetzungen mit einem polymeren Träger (z. B. Rinkamid-Harz) oder einer Schutzgrup- pe (z. B. 2, 4-Dimethoxybenzyl) geschützt, die in der letzten Stufe nach dem Fachmann bekannten Bedingungen abgespalten wird, um zu Verbindungen der Formel (I) zu gelangen.The amide function of the compounds of the formulas (H) 3 (IV), (VI) and (VH) is optionally during the reactions with a polymeric carrier (eg rinkamide resin) or a protective group (eg 2, 4-dimethoxybenzyl) which is cleaved in the last stage according to conditions known to the person skilled in the art in order to obtain compounds of the formula (I).
Die Verbindungen der Formeln (IH), (V), (VII), (VEH) und (DI) sind bekannt oder lassen sich nach bekannten Verfahren aus den entsprechenden Edukten synthetisieren.The compounds of the formulas (IH), (V), (VII), (VEH) and (DI) are known or can be synthesized by known processes from the corresponding starting materials.
Die Herstellung der erfindungsgemäßen Verbindungen kann durch folgendes Syntheseschema ver- deutlicht werden. Schema;The preparation of the compounds according to the invention can be illustrated by the following synthesis scheme. scheme;
H2OH 2 O
Die erfindungsgemäßen Verbindungen zeigen ein nicht vorhersehbares, wertvolles pharma¬ kologisches Wirkspektrum. The compounds of the invention show an unpredictable, valuable pharmacological spectrum of action.
Sie eignen sich daher zur Verwendung als Arzneimittel zur Behandlung und/oder Prophylaxe von Krankheiten bei Menschen und Tieren.They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
Die pharmazeutische Wirksamkeit der erfindungsgemäßen Verbindungen lässt sich durch ihre Wir¬ kung als DL-8-Rezeptor Antagonisten erklären.The pharmaceutical activity of the compounds according to the invention can be explained by their action as DL-8 receptor antagonists.
Weiterer Gegenstand der vorliegenden Erfindung ist der Einsatz der erfindungsgemäßen Verbin¬ dungen zur Behandlung und/oder Prophylaxe von Erkrankungen, vorzugsweise von Haut-, Atem¬ wegs- und Herz-Kreislauf-Erkrankungen, insbesondere von Arteriosklerose.The present invention further provides for the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably skin, respiratory and cardiovascular diseases, in particular arteriosclerosis.
Die Verbindungen der Erfindung sind geeignet für die Behandlung und Prävention von IL-8 ausge¬ lösten, inflammatorischen Prozessen, die Hauterkrankungen (z.B. Psoriasis, (atopische) Dermatitis, Akne, Ekzeme), Atemwegserkrankungen (z.B. Asthma, Bronchitis, chronische obstruktive Lun¬ generkrankung, Atemnotsyndrom), Herzkreislauf-Erkrankungen (z.B. Arteriosklerose, Dyslipidä- mien, Herzinfarkt, Schlaganfall, Restenose, Reperfusionsverletzung, Thrombose, Ischämie, koro- nare Herzerkrankungen, (pulmonale) Hypertension, (Links/Rechts-)Herzinsuffizienz, Arrhythmien, (stabile/instabile) Angina pectoris) und Infektionen (z.B. mit Plasmodien, Hepatitis- und Herpes- Viren), sowie Arthritis (z.B. Osteoarthritis, rheumatoide Arthritis), Osteoporose, Crohn-Krankheit, entzündliche Darmerkrankung (z.B. Colitis ulcerosa), Alzheimer-Krankheit, Sepsis, Gingivitis, Schocks (z.B. septischer Schock, endotoxischer Schock, gram-negativer Schock), Niereninsuffϊ- zienz, (Glumerulo-)Nephritis, Sinusitis, Pankreatitis, Meningitis, Enzephalitis, Transplantat-Wirt- Reaktion, Multiple Sklerose, hyperoxia-induzierte Entzündungen, Autoimmun-Erkrankungen, Gicht, Allergien, Fibrose (z.B. Leberfibrose, Lungenfibrose, zystische Fibrose), Ödembildung, Diabetes, Emphysem und Krebs (z.B. Lungenkrebs, Neoplasma) einschließen.The compounds of the invention are suitable for the treatment and prevention of IL-8-triggered inflammatory processes, the skin diseases (eg psoriasis, (atopic) dermatitis, acne, eczema), respiratory diseases (eg asthma, bronchitis, chronic obstructive pulmonary disease , Respiratory distress syndrome), cardiovascular diseases (eg arteriosclerosis, dyslipidaemia, myocardial infarction, stroke, restenosis, reperfusion injury, thrombosis, ischaemia, coronary heart disease, pulmonary hypertension, left / right heart failure, arrhythmias, unstable angina pectoris) and infections (eg with plasmodia, hepatitis and herpes viruses), as well as arthritis (eg osteoarthritis, rheumatoid arthritis), osteoporosis, Crohn's disease, inflammatory bowel disease (eg ulcerative colitis), Alzheimer's disease, sepsis, Gingivitis, shocks (eg septic shock, endotoxic shock, gram-negative shock), renal insufficiency, (glumerulo-) nephritis, sinusitis s, pancreatitis, meningitis, encephalitis, graft-versus-host disease, multiple sclerosis, hyperoxia-induced inflammation, autoimmune diseases, gout, allergies, fibrosis (e.g. Liver fibrosis, pulmonary fibrosis, cystic fibrosis), edema formation, diabetes, emphysema, and cancer (e.g., lung cancer, neoplasm).
Die erfindungsgemäßen Verbindungen können aufgrund ihrer pharmakologischen Eigenschaften allein und bei Bedarf auch in Kombination mit anderen Wirkstoffen, insbesondere mit anti- hyperlipidämischen, anti-arteriosklerotischen, anti-diabetischen, anti-entzündlichen oder anti¬ hypertensiven Wirkstoffen eingesetzt werden. Beispiele dafür sind Cholesterol-Synthese- Inhibitoren wie z.B. Statine wie z.B. Simvastatin, Pravastatin und Atorvastatin, Antioxidantien wie z.B. Probucol, AGIl 067 und Bo653, PPAR Modulatoren, Fibrate wie z.B. Gemfibrozil und Feno- fibrat, Cholesterol-Absorptionshemmer wie z.B. Ezetimibe, Gallensäureharze wie z.B. Cholesty- ramin und Colesevelam, AcetylCoA-Acyltranferase (ACAT)-Inhibitoren, Cholesterinester- Transferprotein (CETP)-Inhibitoren, Mikrosomales Transferprotein (MTP)/ApolipoproteinB- Sekretions-Inhibitoren, ileale Gallensäure-transporter (IBAT)-Inhibitoren, Niacin und seine slow- release Formen, Insulin (tierischen, menschlichen oder biotechnologischen Ursprungs und Gemi¬ sche davon), Insulin-Sensitizer, Calcium-Kanal-Antagonisten vom z.B. Dihydropyridin-Typ, Dilti- azem-Typ und Verapamil-Typ, ACE Inhibitoren wie z.B. Captopril, Enalapril, Ramipril und Lisi- nopril, Angiotensin II Rezeptor Antagonisten wie z.B. Valsartan, Losartan und Telmisartan, Al- dosteron-Rezeptor Antagonisten wie z.B. Spironolacton und Eplerenon, Beta-Blocker wie z.B. Atenolol, Propanolol, Bisoprolol und Metoprolol, Diuretika wie z.B. Thiazide, kaliumsparende Diuretika und Schleifendiuretika, Digitalis-Glykoside, Nitrate oder NO-Donatoren wie z.B. Isosor¬ bidmononitrat, Isosorbiddinitrat, Aspirin, Kalium-Supplement, Antidiabetika wie z.B. Sulfonyl- harnstoffe und Biguanidine, CBl Antagonisten, Antiarrhythmika und nicht-steroidale Antirheuma¬ tika.Because of their pharmacological properties, the compounds according to the invention can be used alone and if necessary also in combination with other active substances, in particular with anti-hyperlipidemic, anti-arteriosclerotic, anti-diabetic, anti-inflammatory or anti-hypertensive agents. Examples include cholesterol synthesis inhibitors such as statins such as simvastatin, pravastatin and atorvastatin, antioxidants such as probucol, AGIl 067 and Bo653, PPAR modulators, fibrates such as gemfibrozil and fenofibrate, cholesterol absorption inhibitors such as ezetimibe, bile acid resins such as eg cholestyramine and colesevelam, acetylCoA acyltranferase (ACAT) inhibitors, cholesterol ester transfer protein (CETP) inhibitors, microsomal transfer protein (MTP) / apolipoprotein B- Secretion inhibitors, ileal bile acid transporter (IBAT) inhibitors, niacin and its slow-release forms, insulin (of animal, human or biotechnological origin and mixtures thereof), insulin sensitizers, calcium channel antagonists of, for example, dihydropyridine Type, diltiazeme type and verapamil type, ACE inhibitors such as captopril, enalapril, ramipril and lisinopril, angiotensin II receptor antagonists such as valsartan, losartan and telmisartan, aldosterone receptor antagonists such as spironolactone and eplerenone, Beta-blockers such as atenolol, propranolol, bisoprolol and metoprolol, diuretics such as thiazides, potassium-sparing diuretics and loop diuretics, digitalis glycosides, nitrates or NO donors such as Isosor¬ bidmononitrate, isosorbide dinitrate, aspirin, potassium supplement, antidiabetics such as sulfonyl ureas and biguanidines, CB1 antagonists, antiarrhythmics and non-steroidal antirheumatic agents.
Weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung der erfindungsgemäßen Ver¬ bindungen zur Behandlung und/oder Prophylaxe von Erkrankungen, insbesondere der zuvor ge¬ nannten Erkrankungen.Another object of the present invention is the use of Ver¬ compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned ge diseases.
Weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung der erfindungsgemäßen Ver¬ bindungen zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von Erkran¬ kungen, insbesondere der zuvor genannten Erkrankungen.Another object of the present invention is the use of Ver¬ compounds of the invention for the preparation of a medicament for the treatment and / or prophylaxis of Erkran¬ kung, in particular the aforementioned diseases.
Weiterer Gegenstand der vorliegenden Erfindung sind Interleukin-8 Rezeptor Antagonisten zur Behandlung und/oder Prophylaxe von Herzinsuffizienz.Another object of the present invention are interleukin-8 receptor antagonists for the treatment and / or prophylaxis of heart failure.
Weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung eines Interleukin-8 Rezeptor Antagonisten zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von Herz¬ insuffizienz.Another object of the present invention is the use of an interleukin-8 receptor antagonist for the manufacture of a medicament for the treatment and / or prophylaxis of cardiac insufficiency.
Weiterer Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Behandlung und/oder Pro¬ phylaxe von Erkrankungen, insbesondere der zuvor genannten Erkrankungen, unter Verwendung einer therapeutisch wirksamen Menge der erfindungsgemäßen Verbindungen.Another object of the present invention is a method for the treatment and / or Pro¬ phylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of the compounds of the invention.
Die erfindungsgemäßen Verbindungen können systemisch und/oder lokal wirken. Zu diesem Zweck können sie auf geeignete Weise appliziert werden, wie z.B. oral, parenteral, pulmonal, na¬ sal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otisch oder als Implantat bzw. Stent.The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, na¬ sal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
Für diese Applikationswege können die erfindungsgemäßen Verbindungen in geeigneten Applika¬ tionsformen verabreicht werden. Für die orale Applikation eignen sich nach dem Stand der Technik funktionierende schnell und/oder modifiziert die erfindungsgemäßen Verbindungen abgebende Applikationsformen, die die erfindungsgemäßen Verbindungen in kristalliner und/ oder amorphisierter und/oder gelöster Form enthalten, wie z.B. Tabletten (nicht überzogene oder überzogene Tabletten, beispielsweise mit magensaftresistenten oder sich verzögert auflösenden oder unlöslichen Überzügen, die die Freisetzung der erfϊndungsgemäßen Verbindung kontrollieren), in der Mundhöhle schnell zerfal¬ lende Tabletten oder Filme/Oblaten, Filme/Lyophylisate, Kapseln (beispielsweise Hart- oder Weichgelatinekapseln), Dragees, Granulate, Pellets, Pulver, Emulsionen, Suspensionen, Aerosole oder Lösungen.For these administration routes, the compounds according to the invention can be administered in suitable administration forms. For the oral administration, the prior art is capable of rapidly and / or modifying the compounds according to the invention which release the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, for example tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules in the oral cavity Pellets, powders, emulsions, suspensions, aerosols or solutions.
Die parenterale Applikation kann unter Umgehung eines Resorptionsschrittes geschehen (z.B. intravenös, intraarteriell, intrakardial, intraspinal oder intralumbal) oder unter Einschaltung einer Resorption (z.B. intramuskulär, subcutan, intracutan, percutan oder intraperitoneal). Für die paren¬ terale Applikation eignen sich als Applikationsformen u.a. Injektions- und Infusionszubereitungen in Form von Lösungen, Suspensionen, Emulsionen, Lyophilisaten oder sterilen Pulvern.Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For the parenteral application are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
Bevorzugt ist die orale Applikation.The oral application is preferred.
Für die sonstigen Applikationswege eignen sich z.B. Inhalationsarzneiformen (u.a. Pulverinhala¬ toren, Nebulizer), Nasentropfen, -lösungen, -sprays; lingual, sublingual oder buccal zu applizie¬ rende Tabletten, Filme/Oblaten oder Kapseln, Suppositorien, Ohren- oder Augenpräparationen, Vaginalkapseln, wässrige Suspensionen (Lotionen, Schüttelmixturen), lipophile Suspensionen, Salben, Cremes, transdermale therapeutische Systeme (wie beispielsweise Pflaster), Milch, Pasten, Schäume, Streupuder, Implantate oder Stents.For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), Milk, pastes, foams, scattering powders, implants or stents.
Die erfindungsgemäßen Verbindungen können in die angeführten Applikationsformen überführt werden. Dies kann in an sich bekannter Weise durch Mischen mit inerten, nichttoxischen, pharma¬ zeutisch geeigneten Hilfsstoffen geschehen. Zu diesen Hilfsstoffen zählen u.a. Trägerstoffe (bei- spielsweise mikrokristalline Cellulose, Laktose, Mannitol), Lösungsmittel (z.B. flüssige PoIy- ethylenglycole), Emulgatoren und Dispergier- oder Netzmittel (beispielsweise Natrium- dodecylsulfat, Polyoxysorbitanoleat), Bindemittel (beispielsweise Polyvinylpyrrolidon), synthe¬ tische und natürliche Polymere (beispielsweise Albumin), Stabilisatoren (z.B. Antioxidantien wie beispielsweise Ascorbinsäure), Farbstoffe (z.B. anorganische Pigmente wie beispielsweise Eisen- oxide) und Geschmacks- und / oder Geruchskorrigentien.The compounds according to the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. 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, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers ( for example, albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.
Weiterer Gegenstand der vorliegenden Erfindung sind Arzneimittel, die mindestens eine erfin¬ dungsgemäße Verbindung, üblicherweise zusammen mit einem oder mehreren inerten, nichttoxi- schen, pharmazeutisch geeigneten Hilfsstoffen enthalten, sowie deren Verwendung zu den zuvor genannten Zwecken.A further subject of the present invention are medicaments which comprise at least one compound according to the invention, usually together with one or more inert, non-toxic compounds. rule, contain pharmaceutically suitable excipients, and their use for the purposes mentioned above.
Im Allgemeinen hat es sich als vorteilhaft erwiesen, bei parenteraler Applikation Mengen von etwa 0.001 bis 100 mg/kg Körpergewicht je 24 Stunden zur Erzielung wirksamer Ergebnisse zu verab- reichen. Bei oraler" Applikation beträgt die Menge etwa 0.01 bis 250 mg/kg Körpergewicht je 24 Stunden. Bei dermaler Applikation beträgt die Menge etwa 0.1 bis 150 mg/kg Körpergewicht je 24 Stunden.In general, it has proven to be advantageous to administer amounts of about 0.001 to 100 mg / kg of body weight per 24 hours for achieving effective results when administered parenterally. For oral "application, the amount per 24 hours of about 0.01 to 250 mg / kg body weight. In the case of dermal application, the amount is about 0.1 to 150 mg / kg body weight per 24 hours.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit von Körpergewicht, Applikationsweg, individuellem Verhalten gegenüber dem Wirkstoff, Art der Zubereitung und Zeitpunkt bzw. Intervall, zu welchem die Applikation erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindest¬ menge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muss. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen.Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to make do with less than the aforementioned Mindest¬ amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.
Die Prozentangaben in den folgenden Tests und Beispielen sind, sofern nicht anders angegeben, Gewichtsprozente; Teile sind Gewichtsteile. Lösungsmittelverhältnisse, Verdünnungsverhältnisse und Konzentrationsangaben von flüssig/flüssig-Lösungen beziehen sich jeweils auf das Volumen. Die Angabe "w/v" bedeutet "weight/volume" (Gewicht/Volumen). So bedeutet beispielsweise "10% w/v": 100 ml Lösung oder Suspension enthalten 10 g Substanz. The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. The term "w / v" means "weight / volume". Thus, for example, "10% w / v" means: 100 ml of solution or suspension contains 10 g of substance.
A) BeispieleA) Examples
Abkürzungen:Abbreviations:
Abs. absolutAbsolute
ATP AdenosintriphosphatATP adenosine triphosphate
Boc tert.-ButoxycarbonylBoc tert-butoxycarbonyl
BSA Bovines Serum AlbuminBSA Bovine Serum Albumin
CDCl3 DeuterochloroformCDCl 3 deuterochloroform
CO2 KohlendioxidCO 2 carbon dioxide
DC DünnschichtchromatographieTLC thin layer chromatography
DCM DichlormethanDCM dichloromethane
DIEA N,N-DiisopropylethylaminDIEA N, N-diisopropylethylamine
DMEM Dulbecco's Modified Essentiell MediumDMEM Dulbecco's Modified Essentiell Medium
DMSO Dimethylsulfoxid d. Th. der TheorieDMSO dimethyl sulfoxide d. Th. Of theory
EDC N'-(3-Dimethylaminopropyl)-N-ethylcarbodiimidEDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide
EDTA Ethylendiamintetraessigsäure (Ethylene Diamine Tetraacetic Acid) eq. ÄquivalentEDTA ethylenediaminetetraacetic acid (Ethylene Diamine Tetraacetic Acid) eq. equivalent to
ESI Elektrospray-Ionisation (bei MS)ESI electrospray ionization (in MS)
FCS Fetal CaIf Serum (Fötales Kälberserum)FCS Fetal CaIf Serum (Fetal Calf Serum)
Fmoc Fluorenylmethoxycarbonyl ges. gesättigt h StundeFmoc fluorenylmethoxycarbonyl sat. saturated h hour
HOBt 1 -Hydroxy- 1 H-benzotriazolHOBt 1 -Hydroxy- 1 H-benzotriazole
HPLC Hochdruck-, Hochleistungsflüssigchromatographie konz. konzentriertHPLC high pressure, high performance liquid chromatography conc. concentrated
LC-MS Flüssigchromatographie-gekoppelte MassenspektroskopieLC-MS liquid chromatography-coupled mass spectrometry
Min. MinutenMin. Minutes
MS MassenspektroskopieMS mass spectroscopy
MW Molekulargewicht [g/mol]MW molecular weight [g / mol]
NMR KernresonanzspektroskopieNMR nuclear magnetic resonance spectroscopy
PBS Phosphate Buffered Saline (Phosphatgepufferte Νatriumchlorid lösung)PBS Phosphate Buffered Saline (Phosphate Buffered Sodium Chloride Solution)
PMNL Polymorphonuclear Leukocytes (polymorphkernige Leukozyten)PMNL polymorphonuclear leukocytes (polymorphonuclear leukocytes)
Rf Retentionsindex (bei DC) RP-HPLC Reverse Phase HPLCR f retention index (at DC) RP-HPLC reverse phase HPLC
RT RaumtemperaturRT room temperature
R1 Retentionszeit (bei HPLC)R 1 retention time (by HPLC)
TFA TrifluoressigsäureTFA trifluoroacetic acid
THF TetrahydrofuranTHF tetrahydrofuran
HPLC und LC-MS Methoden:HPLC and LC-MS methods:
Methode 1 (HPLC): Instrument: HP 1100 mit DAD-Detektion; Säule: Kromasil RP-18, 60 mm xMethod 1 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x
2 mm, 3.5 μm; Eluent A: 5 ml HCIO4/I Wasser, Eluent B: Acetonitril; Gradient: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 6.5 min 90%B; Fluss: 0.75 ml/min; Ofen: 3O0C; UV-Detektion: 210 nm.2 mm, 3.5 μm; Eluent A: 5 ml HCIO 4 / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 3O 0 C; UV detection: 210 nm.
Methode 2 (LC-MS): Gerätetyp MS: Micromass ZQ; Gerätetyp HPLC: HP 1100 Series; UV DAD; Säule: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 1 Wasser + 0.5 ml 50%ige Ameisensäure, Eluent B: 1 1 Acetonitril + 0.5 ml 50%ige Ameisensäure; Gradient: 0.0 min 90%A -» 2.5 min 30%A -> 3.0 min 5%A -» 4.5 min 5%A; Fluss: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; Ofen: 5O0C; UV-Detektion: 210 nm.Method 2 (LC-MS): Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 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; Gradient: 0.0 min 90% A - »2.5 min 30% A -> 3.0 min 5% A -» 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O 0 C; UV detection: 210 nm.
Methode 3 (LC-MS): Instrument MS: Micromass TOF (LCT); Instrument HPLC: 2-Säulen- Schaltung, Waters2690; Säule: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; Eluent A: Wasser + 0.1% Ameisensäure, Eluent B: Acetonitril + 0.1% Ameisensäure; Gradient: 0.0 min 100%A -> 0.2 min 95%A ■» 1.8 min 25%A -» 1.9 min 10%A -> 2.0 min 5%A -» 3.2 min 5%A; Ofen: 4O0C; Fluss: 3.0 ml/min; UV-Detektion: 210 nm.Method 3 (LC-MS): Instrument MS: Micromass TOF (LCT); Instrument HPLC: 2-column circuit, Waters2690; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 95% A ■ »1.8 min 25% A -» 1.9 min 10% A -> 2.0 min 5% A - »3.2 min 5% A; Oven: 4O 0 C; Flow: 3.0 ml / min; UV detection: 210 nm.
Methode 4 (LC-MS): Instrument: Micromass Quattro LCZ mit HPLC Agilent Serie 1100; Säule: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 1 Wasser + 0.5 ml 50%ige Ameisensäure, Eluent B: 1 1 Acetonitril + 0.5 ml 50%ige Ameisensäure; Gradient: 0.0 min 90%A ■> 2.5 min 30%A -> 3.0 min 5%A -» 4.5 min 5%A; Fluss: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; Ofen: 5O0C; UV-Detektion: 208-400 nm.Method 4 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 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; Gradient: 0.0 min 90% A ■ > 2.5 min 30% A -> 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O 0 C; UV detection: 208-400 nm.
Methode 5 (LC-MS): Instrument MS: Waters ZQ 2000; Instrument HPLC: Agilent 1100, 2- Saeulen-Schaltung, Autosampier: HTC PAL ; Saeule: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; Eluent A: Wasser + 0.1% Ameisensaeure, Eluent B: Acetonitril + 0.1% Ameisensaeure; Gradient: 0.0 min 100%A - 0.1 min 95%A - 0.8 min 25%A - 0.9 min 5%A - 1.8 min 5%A - 1.81 min 100%A - 1.9 min 100%A; Ofen: 400C; Fluss: 3.0 ml/min; UV-Detektion: 210 nm. Methode 6 (LC-MS): Gerätetyp MS: Micromass ZQ; Gerätetyp HPLC: Waters Alliance 2795; Säule: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 1 Wasser + 0.5 ml 50%ige Ameisensäure, Eluent B: 1 1 Acetonitril + 0.5 ml 50%ige Ameisensäure; Gradient: 0.0 min 90%A -> 2.5 min 30%A -> 3.0 min 5%A ■» 4.5 min 5%A; Fluss: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; Ofen: 5O0C; UV-Detektion: 210 nm.Method 5 (LC-MS): Instrument MS: Waters ZQ 2000; Instrument HPLC: Agilent 1100, 2-column circuit, Autosampler: HTC PAL; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A - 0.1 min 95% A - 0.8 min 25% A - 0.9 min 5% A - 1.8 min 5% A - 1.81 min 100% A - 1.9 min 100% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm. Method 6 (LC-MS): Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 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; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A ■ »4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O 0 C; UV detection: 210 nm.
Methode 7 (HPLC): Instrument: HP 1100 mit DAD-Detektion; Säule: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent A: 5 ml HCIO4/I Wasser, Eluent B: Acetonitril; Gradient: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 9 min 90%B; Fluss: 0.75 ml/min; Ofen: 300C; UV-Detektion: 210 nm.Method 7 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml HCIO 4 / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.
Allgemeine ArbeitsvorschriftenGeneral working instructions
Allgemeine Arbeitsvorschrift A: Darstellung von Polymer 2General Procedure A: Preparation of Polymer 2
Polymergebundenes 2-Iod-5-nitrobenzamid (Polymer 1; Beispiel 6A) wird in einem 2:1- Lösungsmittelgemisch aus Dioxan und wässriger Natriumcarbonat-Lösung vorgelegt. Man gibt 10 Äquivalente der Boronsäure und 0.1 Äquivalent des Pd-Katalysators hinzu und rührt bei 8O0C über Nacht unter Argon. Es wird abdekantiert und dreimal mit Wasser, dreimal mit DMF, zweimal mit 0.1%igem Natriumpyrrolidinthiocarbamat in einem Lösungsmittelgemisch aus THF und Methanol (5:1) und anschließend je dreimal mit Methanol und DCM im Wechsel gewaschen. Das Polymer wird anschließend im Vakuum getrocknet.Polymer-bound 2-iodo-5-nitrobenzamide (Polymer 1, Example 6A) is initially charged in a 2: 1 solvent mixture of dioxane and aqueous sodium carbonate solution. Add 10 equivalents of boronic acid and 0.1 equivalent of the Pd catalyst and stir at 8O 0 C overnight under argon. It is decanted off and washed three times with water, three times with DMF, twice with 0.1% sodium pyrrolidinethiocarbamate in a solvent mixture of THF and methanol (5: 1) and then alternately three times with methanol and DCM alternately. The polymer is then dried in vacuo.
Eine Probeabspaltung mit DCM/TFA 1 :1 ergibt das korrespondierende primäre Nitrobenzamid.A sample cleavage with DCM / TFA 1: 1 gives the corresponding primary nitrobenzamide.
Allgemeine Arbeitsvorschrift B: Darstellung von Polymer 3General Procedure B: Preparation of Polymer 3
Polymer 2 wird mit einer 2-molaren Zinndichlorid-Lösung in DMF (65 Äquivalente) versetzt und über Nacht bei RT geschüttelt. Man dekantiert ab, wäscht je dreimal mit DMF, Methanol und DCM und trocknet im Vakuum.Polymer 2 is added to a 2 molar tin dichloride solution in DMF (65 equivalents) and shaken overnight at RT. It is decanted off, washed three times each with DMF, methanol and DCM and dried in vacuo.
Eine Probeabspaltung mit DCM/TFA 1 : 1 ergibt das korrespondierende Anilin.A sample cleavage with DCM / TFA 1: 1 gives the corresponding aniline.
Allgemeine Arbeitsvorschrift C: Darstellung von Polymer 4General Procedure C: Preparation of Polymer 4
Polymer 3 wird in DCM vorgelegt. Man gibt 10 Äquivalente DIEA und 5 Äquivalente des Carbon¬ säurechlorids hinzu und schüttelt über Nacht bei RT. Man dekantiert, wäscht dreimal mit DMF und anschließend dreimal mit Methanol und DCM im Wechsel und trocknet das Polymer im Va¬ kuum. Man versetzt mit einem 2:1 -Gemisch aus Dioxan und einer Lösung aus 5 Äquivalenten Ka¬ liumhydroxid in Methanol und schüttelt über Nacht bei RT. Man filtriert das Polymer ab und wäscht das Polymer dreimal mit Wasser und DMF und anschließend dreimal mit Methanol und DCM im Wechsel. Man trocknet das Polymer im Vakuum.Polymer 3 is presented in DCM. Add 10 equivalents of DIEA and 5 equivalents of carbonic acid chloride and shake overnight at RT. It is decanted, washed three times with DMF and then three times with methanol and DCM and the polymer is dried in vacuo. It is mixed with a 2: 1 mixture of dioxane and a solution of 5 equivalents Ka¬ liumhydroxid in methanol and shaken overnight at RT. The polymer is filtered off and The polymer washes three times with water and DMF and then alternately three times with methanol and DCM. The polymer is dried in vacuo.
Allgemeine Arbeitsvorschrift D: Abspaltung des Produkts vom Polymer 4General Procedure D: Cleavage of the product from the polymer 4
Polymer 4 wird mit konzentrierter TFA versetzt. Man lässt eine Stunde stehen und filtriert vom Polymer ab. Anschließend wird das Polymer mit einem l:l-Gemisch aus TFA und DCM versetzt und erneut eine Stunde stehen gelassen. Man filtriert erneut vom Polymer ab und wäscht das Po¬ lymer zweimal mit dem l:l-Gemisch aus TFA und DCM. Die vereinigten Filtrate werden im Va¬ kuum eingedampft und das so erhaltene Rohprodukt wird mittels präparativer HPLC gereinigt. Polymer 4 is treated with concentrated TFA. It is allowed to stand for an hour and filtered from the polymer. Subsequently, the polymer is mixed with a 1: 1 mixture of TFA and DCM and allowed to stand again for one hour. It is again filtered from the polymer and the polymer is washed twice with the 1: 1 mixture of TFA and DCM. The combined filtrates are evaporated in vacuo and the crude product thus obtained is purified by preparative HPLC.
Ausgangsverbindungenstarting compounds
Nicht kommerziell verfügbare 2-(Het)arylessigsäuren können durch Lithiierung mit LDA oder LiHMTS und anschließende Alkylierung mit einem Alkylhalid synthetisiert werden, siehe Thomp¬ son, H.W.; Rashid, S.Y. J. Org. Chem. 2002, 67, 2813-2825.Non-commercially available 2- (het) arylacetic acids can be synthesized by lithiation with LDA or LiHMTS and subsequent alkylation with an alkyl halide, see Thompson, H.W .; Rashid, S.Y. J. Org. Chem. 2002, 67, 2813-2825.
Beispiel IAExample IA
2-Iod-5-nitrobenzoesäure2-iodo-5-nitrobenzoic acid
Zur Herstellung vergleiche z. B. N. G. Kundu, W. M. Khan, Tetrahedron 2000, 56 (27), 4777- 4792.For making comparisons z. Kundu, W.M. Khan, Tetrahedron 2000, 56 (27), 4777-4792.
HPLC (Methode 1): Rt= 3.85 min.HPLC (Method 1): R t = 3.85 min.
1H-NMR (400 MHz, DMSO-d6): δ = 8.02 (m, IH), 8.30 (m, IH), 8.41 (m, IH), 13.95 (br. s, IH). 1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.02 (m, IH), 8.30 (m, IH), 8.41 (m, IH), 13.95 (br, s, IH).
Beispiel 2AExample 2A
2-Iod-5-nitrobenzoesäurechlorid2-iodo-5-nitrobenzoyl chloride
29.30 g (100 mmol) 2-Iod-5-nitrobenzoesäure werden in einem Lösungsmittelgemisch aus 200 ml DCM und 1 ml DMF als Suspension vorgelegt. Man tropft langsam bei Raumtemperatur 19.04 g (150 mmol, 1.5 Äquivalente) Oxalylchlorid hinzu. Anschließend wird noch zwei Stunden bei Raumtemperatur und 30 min bei 3O0C nachgerührt. Man dampft anschließend am Rotationsver¬ dampfer ein und setzt das so entstandene Rohprodukt in der Folgestufe ein. Beispiel 3A29.30 g (100 mmol) of 2-iodo-5-nitrobenzoic acid are initially charged as a suspension in a solvent mixture of 200 ml of DCM and 1 ml of DMF. 19.04 g (150 mmol, 1.5 equivalents) of oxalyl chloride are slowly added dropwise at room temperature. The mixture is then stirred for a further 2 hours at room temperature and 30 min at 3O 0 C. The mixture is then evaporated on a rotary evaporator and the resulting crude product is used in the subsequent stage. Example 3A
2-Iod-5-nitrobenzamid2-iodo-5-nitrobenzamide
5.0 g (17 mmol) der Verbindung aus Beispiel IA werden in 50 ml Dichlormethan suspendiert. 2.44 g, (20.5 mmol) Thionylchlorid werden hinzugegeben und die Lösung über Nacht (16 h) unter5.0 g (17 mmol) of the compound from Example IA are suspended in 50 ml of dichloromethane. 2.44 g, (20.5 mmol) of thionyl chloride are added and the solution overnight (16 h) under
Rückfluss erhitzt. Das Reaktionsgemisch wird eingeengt und der Rückstand zweimal mit Toluol verrührt und erneut einrotiert. Der Rückstand wird in 30 ml Dioxan suspendiert und langsam zu einer auf 00C gekühlten Lösung von 25%igem Ammoniak in Wasser (50 ml) getropft. Nach derReflux heated. The reaction mixture is concentrated and the residue is stirred twice with toluene and evaporated again. The residue is suspended in 30 ml of dioxane and slowly added dropwise to a cooled to 0 0 C solution of 25% ammonia in water (50 ml). After
Zugabe des Säurechlorids wird das Reaktionsgemisch 1 Stunde bei O0C gerührt, dann auf Raum- temperatur erwärmt und 30 Minuten weitergerührt. Der ausgefallene Niederschlag wird abgesaugt und in vacuo getrocknet. Man erhält 5.0 g (100% d .Th.) der Titelverbindung.Addition of the acid chloride, the reaction mixture is stirred for 1 hour at 0 0 C, then warmed to room temperature and stirred for 30 minutes. The precipitate is filtered off with suction and dried in vacuo. 5.0 g (100% of theory) of the title compound are obtained.
HPLC (Methode 1): R1 = 3.21 min, Xn13x = 196 nm und 300 nmHPLC (method 1): R 1 = 3.21 min, X n13x = 196 nm and 300 nm
MS (DCI): m/z = 293 [M+H]+.MS (DCI): m / z = 293 [M + H] + .
1H-NMR (300 MHz, DMSOd6): δ = 8.19 (d, IH), 8.07 (d, 2H), 7.98-7.91 (m, IH), 7.80 (s, IH). 1 H NMR (300 MHz, DMSOd 6 ): δ = 8.19 (d, IH), 8.07 (d, 2H), 7.98-7.91 (m, IH), 7.80 (s, IH).
Beispiel 4AExample 4A
5-Amino-2-iodobenzamid5-Amino-2-iodobenzamid
Zu einer Lösung von 4.9 g (16.8 mmol) der Verbindung aus Beispiel 3 A in 200 ml DMF werdenTo a solution of 4.9 g (16.8 mmol) of the compound from Example 3A in 200 ml of DMF
15.1 g (67 mmol) Zinn(II)chloriddihydrat gegeben. Das Reaktionsgemisch wird bei 5O0C eine Stunde gerührt, dann wird das DMF in vacuo entfernt. Der Rückstand wird zwischen 1 1 Essigsäu- reethylester und Wasser verteilt, die Phasen werden getrennt, und die organische Phase verworfen. Die wässrige Phase wird mit 10%iger Natronlauge basisch gestellt, und erneut mit 500 ml Essig- säureethylester extrahiert. Das Produkt wird über Magnesiumsulfat getrocknet, abgesaugt und in vacuo eingeengt. Man erhält 3.95 g (90% d. Th.) der Titelverbindung, die ohne weitere Reinigung in der nächsten Stufe umgesetzt wird.Added 15.1 g (67 mmol) stannous chloride dihydrate. The reaction mixture is stirred for one hour at 5O 0 C, then the DMF was removed in vacuo. The residue is partitioned between 1 liter of ethyl acetate and water, the phases are separated and the organic phase is discarded. The aqueous phase is basified with 10% sodium hydroxide solution and extracted again with 500 ml of ethyl acetate. The product is dried over magnesium sulfate, filtered off with suction and concentrated in vacuo. This gives 3.95 g (90% of theory) of the title compound, which is reacted without further purification in the next stage.
LC-MS (Methode 2): R4 = 0.92 minLC-MS (Method 2): R 4 = 0.92 min
MS (ESI): m/z = 263 [M+H]+ MS (ESI): m / z = 263 [M + H] +
1H-NMR (400 MHz, DMSOd6): δ = 5.39 (s, 2H), 6.37 (dd, IH), 6.56 (d, IH), 7.30 (s, IH)5 7.48 (d, IH), 7.64 (s, IH). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 5.39 (s, 2H), 6.37 (dd, IH), 6.56 (d, IH), 7.30 (s, IH) 5 7.48 (d, IH), 7.64 (s, IH).
Beispiel 5AExample 5A
2-Iod-5-[(2-phenylbutanoyl)amino]benzamid2-iodo-5 - [(2-phenylbutanoyl) amino] benzamide
0.823 g (3.14 mmol) der Verbindung aus Beispiel 4A werden in 10 ml Dichlormethan bei RT ge¬ löst und mit 0.688 mg (3.77 mmol) 2-Phenylbuttersäurechlorid und 0.298 mg (3.77 mmol) Pyridin versetzt. Man last über nach bei RT rühren. Man gibt Essigsäureethylester dazu und extrahiert mit Wasser. Die organischen Phasen werden über Magnesiumsulfat getrocknet und bei vermindertem Druck vom Lösungsmittel befreit. Der Rückstand wird über eine Kieselgelsäule chroma¬ tographisch gereinigt (Laufmittel EssigsäureethylesteπCyclohexan 2:1). Man erhält 0.943 g (72% d. Th.) Produkt.0.823 g (3.14 mmol) of the compound from Example 4A are dissolved in 10 ml of dichloromethane at RT and treated with 0.688 mg (3.77 mmol) of 2-phenylbutyric acid chloride and 0.298 mg (3.77 mmol) of pyridine. Keep stirring at RT. Add ethyl acetate and extract with water. The organic phases are dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue is purified by chromatography over a silica gel column (mobile phase ethyl acetate-cyclohexane 2: 1). This gives 0.943 g (72% of theory) of product.
HPLC (Methode 1): R, = 4.15 min.HPLC (Method 1): R, = 4.15 min.
MS (DCI): m/z = 426.3 [M+HJ+.MS (DCI): m / z = 426.3 [M + HJ + .
1H-NMR (300 MHz, DMSO-d6): δ = 0.85 (t, 3H), 1.70 undl.96-2.13 (m0 und m, AB-Signal, 2H), 3.55 (dd, IH), 7.20-7.42 (m, 6H), 7.47 (s, IH), 7.65 (d, IH), 7.74 (d, IH), 7.79 (s, IH), 10.25 (s, IH). Beispiel 6A 1 H-NMR (300 MHz, DMSO-d 6 ): δ = 0.85 (t, 3H), 1.70 and 0.96-2.13 (m 0 and m, AB signal, 2H), 3.55 (dd, IH), 7.20 -7.42 (m, 6H), 7.47 (s, IH), 7.65 (d, IH), 7.74 (d, IH), 7.79 (s, IH), 10.25 (s, IH). Example 6A
Polymergebundenes 2-Iod-5-nitrobenzamid (Polymer 1)Polymer bound 2-iodo-5-nitrobenzamide (Polymer 1)
Man versetzt 4.0 g (3.092 mmol) Fmoc-Rinkamid (0.77 mmol/g, Rapp Polymere) mit 20 ml eines 4:1-Gemischs aus DMF und Piperidin. Es wird 30 min bei RT geschüttelt. Das Polymer wird an¬ schließend über eine Fritte abgesaugt, dreimal mit DMF und anschließend dreimal mit Methanol und DCM im Wechsel gewaschen und im Vakuum getrocknet. Das derart entschützte Rinkamid- Polymer hat nun eine Beladung von 0.93 mmol/g.4.0 g (3.092 mmol) of Fmoc-Rinkamide (0.77 mmol / g, Rapp Polymere) are added to 20 ml of a 4: 1 mixture of DMF and piperidine. It is shaken for 30 min at RT. The polymer is subsequently filtered off with suction through a frit, washed three times with DMF and then three times with methanol and DCM and dried in vacuo. The thus deprotected Rinkamid- polymer now has a loading of 0.93 mmol / g.
Man suspendiert das entschützte Rinkamid-Polymer in 20 ml DCM und 2.00 g (1.55 mmol, 2 Ä- quivalente) DIEA und gibt anschließend 1.93 g (6.18 mmol, 2 Äquivalente) 2-Iod-5- nitrobenzoesäurechlorid (Beispiel 2A) hinzu. Es wird über Nacht bei Raumtemperatur geschüttelt. Anschließend wird je dreimal mit DMF, Methanol und DCM gewaschen. Das so entstandene Po¬ lymer 1 wird im Vakuum getrocknet.The deprotected Rinc amide polymer is suspended in 20 ml DCM and 2.00 g (1.55 mmol, 2 equivalents) of DIEA and then 1.93 g (6.18 mmol, 2 equivalents) of 2-iodo-5-nitrobenzoic acid chloride (Example 2A) are added. It is shaken overnight at room temperature. It is then washed three times each with DMF, methanol and DCM. The resulting polymer 1 is dried in vacuo.
Beispiel 7AExample 7A
2-( 1 -Benzothien-2-yl)-5-nitrobenzamid2- (1-benzothien-2-yl) -5-nitrobenzamide
2-Iod-5-nitrobenzamid (Beispiel 3A; 6.56 g) wird in Dioxan (130 ml) und ges. Natriumcarbonat- Lösung (65 ml) vorgelegt, mit Benzothiophen-2-boronsäure (6.00 g) und Dichlor- bis(triphenylphosphin)palladium (1.58 g) versetzt und über Nacht bei 8O0C nachgerührt. Das Re¬ aktionsgemisch wird über Kieselgur filtriert und mit Ethylacetat (250 ml) und Wasser (100 ml) nachgewaschen. Die organische Phase wird mit Wasser (dreimal 100 ml) und ges. Natriumchlorid- Lösung (100 ml) extrahiert und anschließend über Natriumsulfat getrocknet und einrotiert. Der Rückstand wird auf Kieselgel chromatographiert (CyclohexaniEthylacetat 10:1 — > reines Ethyl¬ acetat). Nach Einrotieren der Produktfraktionen wird die Zielverbindung in Diethylether aufge¬ schlemmt, abgesaugt und getrocknet. Man erhält 4.75 g Produkt (64% d. Th.). LC-MS (Methode 4): R1 = 2.15 min2-iodo-5-nitrobenzamide (Example 3A; 6.56 g) is dissolved in dioxane (130 ml) and sat. Sodium carbonate solution (65 ml), treated with benzothiophene-2-boronic acid (6.00 g) and dichloro-bis (triphenylphosphine) palladium (1.58 g) and stirred at 8O 0 C overnight. The reaction mixture is filtered through kieselguhr and washed with ethyl acetate (250 ml) and water (100 ml). The organic phase is washed with water (three times 100 ml) and sat. Sodium chloride solution (100 ml) and then dried over sodium sulfate and concentrated by rotary evaporation. The residue is chromatographed on silica gel (cyclohexane ethyl acetate 10: 1 → pure ethyl acetate). After rotary evaporation of the product fractions, the target compound is suspended in diethyl ether, filtered off with suction and dried. 4.75 g of product (64% of theory) are obtained. LC-MS (Method 4): R 1 = 2.15 min
MS (ESI): m/z = 297 [M-H]-MS (ESI): m / z = 297 [M-H] -
Beispiel 8AExample 8A
5 -Amino-2-( 1 -benzothien-2-y l)benzamid5-amino-2- (1-benzothien-2-yl) benzamide
2-(l-Benzothien-2-yl)-5-nitrobenzamid (4.75 g) wird in THF (250 ml) vorgelegt und mit Platindi¬ oxid (0.57 g) versetzt und anschließend bei RT über Nacht bei Normaldruck hydriert. Das Reakti¬ onsgemisch wird über Kieselgur filtriert, mit THF nachgewaschen und die organische Phase ein¬ geengt. Der Rückstand wird mit Diethylether verrührt und die Kristalle abgesaugt. Es wird mit Diethylether und ein wenig DCM nachgewaschen und getrocknet. Ausbeute 2.39 g (56% d. Th.).2- (1-Benzothien-2-yl) -5-nitrobenzamide (4.75 g) is initially charged in THF (250 ml) and treated with platinum oxide (0.57 g) and then hydrogenated at RT under atmospheric pressure overnight. The reaction mixture is filtered through kieselguhr, washed with THF and the organic phase is concentrated by evaporation. The residue is stirred with diethyl ether and the crystals are filtered off with suction. It is washed with diethyl ether and a little DCM and dried. Yield 2.39 g (56% of theory).
LC-MS (Methode 2): R, = 1.91 minLC-MS (Method 2): R, = 1.91 min
MS (ESI): m/z = 269 [M+H]+ MS (ESI): m / z = 269 [M + H] +
Beispiel 9AExample 9A
2-(l-Benzothien-2-yl)-5-[(2-brombutanoyl)amino]benzamid 2- (l-benzothien-2-yl) -5 - [(2-brombutanoyl) amino] benzamide
5-Amino-2-(l-benzothien-2-yl)benzamid (Beispiel 8A, 886 mg) und Triethylamin (650 mg) wer¬ den in DCM (20 ml) bei 00C vorgelegt und 2-Brombuttersäurebromid (1000 mg) wird langsam zugegeben. Das Reaktionsgemisch wird auf RT aufgewärmt und über Nacht weitergerührt. Das Reaktionsgemisch wird anschließend mit DCM (100 ml) verdünnt und mit 5%iger Kaliumhydro¬ gensulfat-Lösung (zweimal 50 ml) gewaschen, getrocknet (Natriumsulfat) und einrotiert. Der Rückstand wird über Kieselgel chromatographiert (Eluent Cyclohexan-Ethylacetat 10:1 bis 1:1). Nach Einengen der relevanten Fraktion werden 607 mg (47% d. Th.) Produkt isoliert.5-Amino-2- (1-benzothien-2-yl) benzamide (Example 8A, 886 mg) and triethylamine (650 mg) wer¬ in DCM (20 ml) at 0 0 C submitted and 2-bromobutyric acid bromide (1000 mg ) is added slowly. The reaction mixture is warmed to RT and stirred overnight. The reaction mixture is then diluted with DCM (100 ml) and washed with 5% potassium hydrogen sulfate solution (twice 50 ml), dried (sodium sulfate) and concentrated by rotary evaporation. The residue is chromatographed on silica gel (eluent cyclohexane-ethyl acetate 10: 1 to 1: 1). After concentrating the relevant fraction, 607 mg (47% of theory) of product are isolated.
LC/MS (Methode 2): R, = 2.33 minLC / MS (method 2): R, = 2.33 min
MS (ESI): m/z = 417 [M+H]+ MS (ESI): m / z = 417 [M + H] +
IH-NMR (400 MHz, DMSOd6): = 10.62 (br s, IH), 7.97 (d, 2H), 7.83 (d, IH), 7.73 (m, 2H), 7.58 (d, IH), 7.52 (s, IH), 7.49 (s, IH), 7.32 (m, 2H), 4.50 (t, IH), 2.11 (m, IH), 1.96 (m, IH), 0.94 (t, 3H). IH-NMR (400 MHz, DMSOd 6 ): = 10.62 (brs, IH), 7.97 (d, 2H), 7.83 (d, IH), 7.73 (m, 2H), 7.58 (d, IH), 7.52 ( s, IH), 7.49 (s, IH), 7.32 (m, 2H), 4.50 (t, IH), 2.11 (m, IH), 1.96 (m, IH), 0.94 (t, 3H).
Ausführungsbeispieleembodiments
Beispiel 1example 1
2-(l-Benzothien-2-yl)-5-[(2-phenylbutanoyl)amino]benzamid2- (l-benzothien-2-yl) -5 - [(2-phenylbutanoyl) amino] benzamide
Eine Lösung von 500 mg (1.23 mmol) der Verbindung aus Beispiel 5A, 262 mg (1.47 mmol) l-Benzothien-2-ylboronsäure, 1.34 ml (2.70 mmol, 2M Lösung in Wasser) Natriumcarbonat und 42 mg (0.061 mmol) Bis(triphenylphosphin)palladium(II)chlorid in 10 ml Dimethoxyethan werden 3 Stunden unter Rückfluss gerührt. Die auf Raumtemperatur abgekühlte Lösung wird zwischen 500 ml Essigsäureethylester und Wasser verteilt, und die wässrige Phase wird zweimal mit 200 ml Essigsäureethylester extrahiert. Die vereinigten organischen Phasen werden mit gesättigter Natri¬ umchlorid-Lösung gewaschen, über Magnesiumsulfat getrocknet, abgesaugt und eingeengt. Der Rückstand wird in Dimethylsulfoxid gelöst und mittels präparativer RP-HPLC mit Acetonitril und Wasser gereinigt. Man erhält 146 mg (29% d. Th.) der Titelverbindung.A solution of 500 mg (1.23 mmol) of the compound of Example 5A, 262 mg (1.47 mmol) of l-benzothien-2-ylboronic acid, 1.34 ml (2.70 mmol, 2M solution in water) of sodium carbonate and 42 mg (0.061 mmol) of bis ( Triphenylphosphine) palladium (II) chloride in 10 ml of dimethoxyethane are stirred under reflux for 3 hours. The cooled to room temperature solution is partitioned between 500 ml of ethyl acetate and water, and the aqueous phase is extracted twice with 200 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered off with suction and concentrated. The residue is dissolved in dimethyl sulfoxide and purified by preparative RP-HPLC with acetonitrile and water. 146 mg (29% of theory) of the title compound are obtained.
LC-MS (Methode 2): R4 = 2.54 minLC-MS (Method 2): R 4 = 2.54 min
MS (ESI): m/z = 415 [M+H]+ MS (ESI): m / z = 415 [M + H] +
1H-NMR (400 MHz3 DMSO-d6): δ = 10.35 (s, IH), 8.00-7.15 (m, 13H), 3.60 (m, IH), 2.15-1.60 (m, 2H), 0.90 (t, 3H). 1 H-NMR (400 MHz 3 DMSO-d 6 ): δ = 10.35 (s, IH), 8.00-7.15 (m, 13H), 3.60 (m, IH), 2.15-1.60 (m, 2H), 0.90 ( t, 3H).
Durch präparative HPLC an chiraler Phase [DAD-Detektion; Säule: KBD 5326 (basierend auf Poly(N-methacryloyl-L-leucin-dicyclopropylmethylamid)), 250 mm x 30 mm; Eluent: Essigsäure- ethylester; Fluss: 40 ml/min; Ofen: 240C; UV-Detektion: 254 nm] werden die Enantiomere ge¬ trennt.By preparative HPLC on a chiral phase [DAD detection; Column: KBD 5326 (based on poly (N-methacryloyl-L-leucine dicyclopropylmethylamide)), 250 mm x 30 mm; Eluent: ethyl acetate; Flow: 40 ml / min; Oven: 24 ° C; UV detection: 254 nm], the enantiomers are separated ge.
Analytische HPLC [DAD-Detektion; Säule: KBD 5326 (basierend auf Poly(N-methacryloyl-L- leucin-dicyclopropylmethylamid)), 250 mm x 4.6 mm; Eluent: Essigsäureethylester; Fluss: 2 ml/min; Ofen: 24°C; UV-Detektion: 270 nm] ergibt folgende Retentionszeiten für die Enantio- mere:Analytical HPLC [DAD detection; Column: KBD 5326 (based on poly (N-methacryloyl-L-leucine dicyclopropylmethylamide)), 250 mm x 4.6 mm; Eluent: ethyl acetate; River: 2 ml / min; Oven: 24 ° C; UV detection: 270 nm] gives the following retention times for the enantiomers:
(■SVEnantiomer 1-1: R, = 3.03 min.(■ SVEnantiomer 1-1: R, = 3.03 min.
(RVEnantiomer 1-2: R1 = 4.07 min.(RVEnantiomer 1-2: R 1 = 4.07 min.
Beispiel 2Example 2
2-(6-Ethoxy-2-naphthyl)-5-[(2-phenylbutanoyl)amino]benzamid2- (6-ethoxy-2-naphthyl) -5 - [(2-phenylbutanoyl) amino] benzamide
Zu 50 mg (0.12 mmol) der Verbindung aus Beispiel 5A in 3 ml Dioxan werden 1.5 ml gesättigte wässrige Natriumcarbonatlösung, 40 mg (0.18 mmol) 6-Ethoxy-2-naphthalinboronsäure und 14 mg (0.01 mmol) Tetrakis(triphenylphosphin)palladium gegeben. Man lässt über Nacht bei 80°C rüh¬ ren, versetzt dann mit 50 ml Essigsäureethylester und extrahiert dreimal mit 50 ml Wasser. Die organische Phase wird über Magnesiumsulfat getrocknet und bei vermindertem Druck vom Lö- sungsmittel befreit. Der Rückstand wird mittels präparativer HPLC gereinigt (Eluens: Aceto- nitril/Wasser mit 0.1% Ameisensäure, Gradient 10:90 -» 95:5). Man erhält 26 mg (44% d. Th.) Produkt.To 50 mg (0.12 mmol) of the compound from Example 5A in 3 ml of dioxane are added 1.5 ml of saturated aqueous sodium carbonate solution, 40 mg (0.18 mmol) of 6-ethoxy-2-naphthalene boronic acid and 14 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium. The mixture is allowed to stir overnight at 80 ° C., then treated with 50 ml of ethyl acetate and extracted three times with 50 ml of water. The organic phase is dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90-> 95: 5). This gives 26 mg (44% of theory) of product.
HPLC (Methode 1): R1 = 4.85 min.HPLC (Method 1): R 1 = 4.85 min.
MS (DCI): m/z = 470.5 [M+NH,]+.MS (DCI): m / z = 470.5 [M + NH,] + .
1H-NMR (300 MHz, DMSOd6): δ = 0.89 (t, 3H), 1.41 (t, 3H), 1.72 und 2.00-2.18 (m0 und m, AB- Signal, 2H), 3.58 (dd, IH), 4.15 (q, 2H), 7.15 (dd, IH), 7.19-7.44 (m, 8 H), 7.16 (dd, IH), 7.65 (s, IH), 7.70-7.85 (m, 5H), 10.30 (s, IH). Beispiel 3 1 H-NMR (300 MHz, DMSOd 6 ): δ = 0.89 (t, 3H), 1.41 (t, 3H), 1.72 and 2.00-2.18 (m 0 and m, AB signal, 2H), 3.58 (dd, IH), 4.15 (q, 2H), 7.15 (dd, IH), 7.19-7.44 (m, 8H), 7.16 (dd, IH), 7.65 (s, IH), 7.70-7.85 (m, 5H), 10.30 (s, IH). Example 3
5-[(2-Phenylbutanoyl)amino]-2-(5-phenyl-2-thienyl)benzamid5 - [(2-phenylbutanoyl) amino] -2- (5-phenyl-2-thienyl) benzamide
Zu 50 mg (0.12 mmol) der Verbindung aus Beispiel 5A in 3 ml Dioxan werden 1.5 ml gesättigte wässrige Natriumcarbonatlösung, 37 mg (0.18 mmol) 5-Phenyl-2-thiophenboronsäure und 14 mg (0.01 mmol) Tetrakis(triphenylphosphin)palladium gegeben. Man lässt über Nacht bei 8O0C rüh¬ ren, versetzt dann mit 50 ml Essigsäureethylester und extrahiert dreimal mit 50 ml Wasser. Die organische Phase wird über Magnesiumsulfat getrocknet und bei vermindertem Druck vom Lö¬ sungsmittel befreit. Der Rückstand wird mittels präparativer HPLC gereinigt (Eluens: Aceto- nitril/Wasser mit 0.1% Ameisensäure, Gradient 10:90 -» 95:5). Man erhält 18 mg (30% d. Th.) Produkt.To 50 mg (0.12 mmol) of the compound from Example 5A in 3 ml of dioxane are added 1.5 ml of saturated aqueous sodium carbonate solution, 37 mg (0.18 mmol) of 5-phenyl-2-thiopheneboronic acid and 14 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium. The mixture is left overnight at 8O 0 C rüh¬ reindeer, then treated with 50 ml of ethyl acetate and extracted three times with 50 ml of water. The organic phase is dried over magnesium sulfate and freed of solvent at reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90-> 95: 5). 18 mg (30% of theory) of product are obtained.
HPLC (Methode 1): R, = 4.87 min.HPLC (Method 1): R, = 4.87 min.
MS (DCI): m/z = 458.4 [M+NHL,]*.MS (DCI): m / z = 458.4 [M + NHL,] *.
1H-NMR (300 MHz, DMSOd6): δ = 0.88 (t, 3H), 1.72 und 1.98-2.17 (mc und m, AB-Signal, 2H), 3.56 (dd, IH), 7.17-7.52 (m, 12H), 7.61-7.72 (m, 4 H), 7.86 (s, IH), 10.34 (s, IH). 1 H-NMR (300 MHz, DMSOd 6 ): δ = 0.88 (t, 3H), 1.72 and 1.98-2.17 (m c and m, AB signal, 2H), 3.56 (dd, IH), 7.17-7.52 ( m, 12H), 7.61-7.72 (m, 4H), 7.86 (s, IH), 10.34 (s, IH).
Beispiel 4Example 4
2-(l-Benzofuran-2-yl)-5-[(2-phenylbutanoyl)amino]benzamid2- (l-benzofuran-2-yl) -5 - [(2-phenylbutanoyl) amino] benzamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5-nitrobenzoe- säurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeits¬ vorschriften A bis D wird anschließend mit 150.7 mg (930 μmol) l-Benzofiiran-2-ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 84.6 mg (465 μmol) 2-Phe- nylbuttersäurechlorid und 120 mg (930 μmol) DIEA 11.9 mg (29.9 μmol; 32% d. Th.) Produkt erhalten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using general working instructions A to D, 150.7 mg (930 μmol) of 1-benzofiiran-2-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 84.6 mg (465 μmol) of 2- Phenylbutyric acid chloride and 120 mg (930 μmol) of DIEA 11.9 mg (29.9 μmol, 32% of theory) of product.
LC-MS (Methode 3): R1 = 2.17 minLC-MS (Method 3): R 1 = 2.17 min
MS (ESI pos): m/z = 399 [M+H]+ MS (ESI pos): m / z = 399 [M + H] +
1H-NMR (400 MHz, DMSOd6): δ = 0.88 (t, 3H), 1.72 und 2.01-2.14 (mc und m, AB-Signal, 2H), 3.59 (dd, IH), 7.10 (s, IH), 7.21-7.43 (m, 7H), 7.53-7.59 (m, 2H), 7.65 (d, IH), 7.71-7.84 (m, 3H), 7.95 (s, IH), 10.38 (s, IH). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 0.88 (t, 3H), 1.72 and 2.01-2.14 (m c and m, AB signal, 2H), 3.59 (dd, IH), 7.10 (s, IH), 7.21-7.43 (m, 7H), 7.53-7.59 (m, 2H), 7.65 (d, IH), 7.71-7.84 (m, 3H), 7.95 (s, IH), 10.38 (s, IH) ,
Beispiel 5Example 5
2-(l,3-Benzodioxol-5-yl)-5-[(2-phenylbutanoyl)amino]benzamid2- (l, 3-benzodioxol-5-yl) -5 - [(2-phenylbutanoyl) amino] benzamide
250 mg (193 μmol) Fmoc-Rinkamid (0.77 mmol/g, Rapp Polymere) wird mit 112.8 mg (385 μmol) 2-Iod-5-nitrobenzoesäurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeitsvorschriften A bis D wird anschließend mit 320.4 mg (1.93 mmol) 1,3- Benzodioxol-5-ylboronsäure, 22.3 mg (19.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 175.6 mg (965 μmol) 2-Phenylbuttersäurechlorid und 249 mg (1.93 mmol) DIEA 33.0 mg (82.1 μmol; 43% d. Th.) Produkt erhalten. 250 mg (193 μmol) of Fmoc-Rinkamide (0.77 mmol / g, Rapp Polymere) is reacted with 112.8 mg (385 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using general procedures A to D, then, with 320.4 mg (1.93 mmol) of 1,3-benzodioxol-5-ylboronic acid, 22.3 mg (19.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 175.6 mg (965 μmol) of 2- Phenylbutyric acid chloride and 249 mg (1.93 mmol) of DIEA 33.0 mg (82.1 μmol, 43% of theory) of product.
LC-MS (Methode 4): R1 = 2.28 minLC-MS (Method 4): R 1 = 2.28 min
MS (ESI pos): m/z = 403 [M+H]+ MS (ESI pos): m / z = 403 [M + H] +
1H-NMR (400 MHz, CDCl3): δ = 7.90-6.80 (m, 1 IH), 6.00 (s, 2H), 5.50 (d, 2H), 3.40 (t, IH), 2.40- 1.70 (m, 2H), 0.90 (t, 3H). 1 H-NMR (400 MHz, CDCl 3): δ = 7.90-6.80 (m, 1 IH) 6.00 (s, 2H), 5.50 (d, 2H), 3:40 (t, IH), 2.40- 1.70 (m , 2H), 0.90 (t, 3H).
Beispiel 6Example 6
2-(l-Benzothien-3-yl)-5-[(2-phenylbutanoyl)amino]benzamid2- (l-benzothien-3-yl) -5 - [(2-phenylbutanoyl) amino] benzamide
250 mg (193 μmol) Fmoc-Rinkamid (0.77 mmol/g, Rapp Polymere) wird mit 112.8 mg (385 μmol) 2-Iod-5-nitrobenzoesäurechlorid zu Polymer 1 umgesetzt. Unter Verwendung der allgemeinen Arbeitsvorschriften A bis D wird anschließend mit 343.6 mg (1.93 mmol) l-Benzothien-3- ylboronsäure, 22.3 mg (19.3 μmol) Tetrakis(triphenylphosphm)palladium(0), 175.6 mg (965 μmol) 2-Phenylbuttersäurechlorid und 249 mg (1.93 mmol) DIEA 18.0 mg (43.5 μmol; 23% d. Th.) Pro¬ dukt erhalten.250 mg (193 μmol) of Fmoc-Rinkamide (0.77 mmol / g, Rapp Polymere) is reacted with 112.8 mg (385 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1. Using general procedures A through D, then, 343.6 mg (1.93 mmol) of l-benzothien-3-ylboronic acid, 22.3 mg (19.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 175.6 mg (965 mmol) of 2-phenylbutyryl chloride and 249 mg (1.93 mmol) of DIEA 18.0 mg (43.5 μmol, 23% of theory) of product were obtained.
LC-MS (Methode 4): Rt = 2.50 minLC-MS (Method 4): R t = 2.50 min
MS (ESI pos): m/z = 415 [M+H]+ MS (ESI pos): m / z = 415 [M + H] +
1H-NMR (400 MHz, CDCl3): δ = 8.10-7.20 (m, 13H), 5.35 (d, 2H), 3.45 (t, IH), 2.40-1.60 (m, 2H), 0.95 (t, 3H). Beispiel 7 1 H-NMR (400 MHz, CDCl 3): δ = 8:10 to 7:20 (m, 13H), 5:35 (d, 2H), 3:45 (t, IH), 2.40-1.60 (m, 2H), 0.95 (t, 3H). Example 7
4-[(2-Phenylbutanoyl)amino]-l , l':4', 1 "-terphenyl-2-carboxamid4 - [(2-phenylbutanoyl) amino] -1, 1 ': 4', 1 "-terphenyl-2-carboxamide
250 mg (193 μmol) Fmoc-Rinkamid (0.77 mmol/g, Rapp Polymere) wird mit 112.8 mg (385 μmol) 2-Iod-5-nitrobenzoesäurechlorid zu Polymer 1 umgesetzt. Unter Verwendung der allgemeinen Arbeitsvorschriften A bis D wird anschließend mit 382.1 mg (1.93 mmol) Biphenyl-4- ylboronsäure, 22.3 mg (19.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 175.6 mg (965 μmol) 2-Phenylbuttersäurechlorid und 249 mg (1.93 mmol) DIEA 36.3 mg (83.6 μmol; 43% d. Th.) Pro¬ dukt erhalten.250 mg (193 μmol) of Fmoc-Rinkamide (0.77 mmol / g, Rapp Polymere) is reacted with 112.8 mg (385 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1. Using general operating procedures A to D, 382.1 mg (1.93 mmol) of biphenyl-4-ylboronic acid, 22.3 mg (19.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 175.6 mg (965 μmol) of 2-phenylbutyryl chloride and 249 mg (1.93 mmol) DIEA 36.3 mg (83.6 μmol, 43% of theory) product.
LC-MS (Methode 4): R, = 2.63 minLC-MS (Method 4): R, = 2.63 min
MS (ESI pos): m/z = 435 [M+H]+ MS (ESI pos): m / z = 435 [M + H] +
1H-NMR (400 MHz, DMSOd6): δ = 7.70-7.20 (m, 17H), 3.60 (t, IH), 2.20-1.60 (m, 2H), 0.90 (t, 3H). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 7.70-7.20 (m, 17H), 3.60 (t, IH), 2.20-1.60 (m, 2H), 0.90 (t, 3H).
Durch präparative HPLC an chiraler Phase [DAD-Detektion; Säule: KBD 5326 (basierend auf Poly(N-methacryloyl-L-leucin-dicyclopropylmethylamid)), 250 mm x 30 mm; Eluent: Essigsäure- ethylester; Fluss: 40 ml/min; Ofen: 240C; UV-Detektion: 254 nm] werden die Enantiomere ge¬ trennt.By preparative HPLC on a chiral phase [DAD detection; Column: KBD 5326 (based on poly (N-methacryloyl-L-leucine dicyclopropylmethylamide)), 250 mm x 30 mm; Eluent: ethyl acetate; Flow: 40 ml / min; Oven: 24 ° C; UV detection: 254 nm], the enantiomers are separated ge.
Analytische HPLC [DAD-Detektion; Säule: KBD 5326 (basierend auf Poly(N-methacryloyl-L- leucin-dicyclopropylmethylamid)), 250 mm x 4.6 mm; Eluent: Essigsäureethylester; Fluss: 2 ml/min; Ofen: 24°C; UV-Detektion: 270 nm] ergibt folgende Retentionszeiten für die Enantiome¬ re:Analytical HPLC [DAD detection; Column: KBD 5326 (based on poly (N-methacryloyl-L-leucine dicyclopropylmethylamide)), 250 mm x 4.6 mm; Eluent: ethyl acetate; Flow: 2 ml / min; Oven: 24 ° C; UV detection: 270 nm] gives the following retention times for the enantiomers:
(.SVEnantiomer 7-l: Rt = 7.67 min. IRVEnantiomer 7-2: R, = 5.59 min.(.SVEnantiomer 7-l: R t = 7.67 min. IRVEnantiomer 7-2: R, = 5.59 min.
Beispiel 8Example 8
3'-Fluor-4-[(2-phenylbutanoyl)amino]-l,r:4',rι-terphenyl-2-carboxamid3'-fluoro-4 - [(2-phenylbutanoyl) amino] -l, r: 4 ', r ι terphenyl-2-carboxamide
250 mg (193 μmol) Fmoc-Rinkamid (0.77 mmol/g, Rapp Polymere) wird mit 112.8 mg (385 μmol) 2-Iod-5-nitrobenzoesäurechlorid zu Polymer 1 umgesetzt. Unter Verwendung der allgemeinen Arbeitsvorschriften A bis D wird anschließend mit 416.9 mg (1.93 mmol) (2-Fluorbiphenyl-4- yl)boronsäure, 22.3 mg (19.3 μmol) Terrakis(triphenylphosphin)palladium(0), 175.6 mg (965 μmol) 2-Phenylbuttersäurechlorid und 249 mg (1.93 mmol) DIEA 10.0 mg (22.1 μmol; 11% d. Th.) Produkt erhalten.250 mg (193 μmol) of Fmoc-Rinkamide (0.77 mmol / g, Rapp Polymere) is reacted with 112.8 mg (385 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1. Using general procedures A to D, then, 416.9 mg (1.93 mmol) of (2-fluorobiphenyl-4-yl) boronic acid, 22.3 mg (19.3 μmol) of terrakis (triphenylphosphine) palladium (0), 175.6 mg (965 mmol) of 2 Phenylbutyric acid chloride and 249 mg (1.93 mmol) of DIEA 10.0 mg (22.1 μmol, 11% of theory) of product.
LC-MS (Methode 4): R, = 2.69 minLC-MS (Method 4): R, = 2.69 min
++
MS (ESI pos): m/z = 453 [M+H]MS (ESI pos): m / z = 453 [M + H]
1H-NMR (400 MHz, CDCl3): δ = 7.90-7.15 (m, 16H), 5.50 (d, 2H), 3.40 (t, IH)5 2.40-1.60 (m, 2H), 0.90 (t, 3H). 1 H-NMR (400 MHz, CDCl 3 ): δ = 7.90-7.15 (m, 16H), 5.50 (d, 2H), 3.40 (t, IH) 5 2.40-1.60 (m, 2H), 0.90 (t, 3H).
Beispiel 9Example 9
2-(2-Naphthyl)-5-[(2-phenylbutanoyl)amino]benzamid2- (2-naphthyl) -5 - [(2-phenylbutanoyl) amino] benzamide
250 mg (193 μmol) Fmoc-Rinkamid (0.77 mmol/g, Rapp Polymere) wird mit 112.8 mg (385 μmol) 2-Iod-5-nitrobenzoesäurechlorid zu Polymer 1 umgesetzt. Unter Verwendung der allgemeinen Arbeitsvorschriften A bis D wird anschließend mit 332.0 mg (1.93 mmol) 2-Naphthylboronsäure, 22.3 mg (19.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 175.6 mg (965 μmol) 2- Phenylbuttersäurechlorid und 249 mg (1.93 mmol) DIEA 40.1 mg (98.3 μmol; 51% d. Th.) Pro¬ dukt erhalten.250 mg (193 μmol) of Fmoc-Rinkamide (0.77 mmol / g, Rapp Polymere) is reacted with 112.8 mg (385 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1. Using general procedure A to D, then 332.0 mg (1.93 mmol) 2-naphthyl boronic acid, 22.3 mg (19.3 μmol) tetrakis (triphenylphosphine) palladium (0), 175.6 mg (965 μmol) 2-phenylbutyrate and 249 mg (1.93 mmol) DIEA 40.1 mg (98.3 μmol, 51% of theory) of product.
LC-MS (Methode 2): R1 = 2.54 minLC-MS (Method 2): R 1 = 2.54 min
MS (ESI pos): m/z = 409 [M+H]+ MS (ESI pos): m / z = 409 [M + H] +
1H-NMR (400 MHz, DMSOd6): δ = 10.30 (s, IH), 8.00-7.20 (m, 15H), 3.60 (t, IH), 2.20-1.60 (m, 2H), 0.90 (t, 3H). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 10.30 (s, IH), 8.00-7.20 (m, 15H), 3.60 (t, IH), 2.20-1.60 (m, 2H), 0.90 (t, 3H).
Beispiel 10Example 10
2-(l-Benzothien-2-yl)-5-[(2-phenylpropanoyl)amino]benzamid2- (l-benzothien-2-yl) -5 - [(2-phenylpropanoyl) amino] benzamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5- nitrobenzoesäurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemei- nen Arbeitsvorschriften A bis D wird anschließend mit 165.5 mg (930 μmol) l-Benzothien-2- ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 78.1 mg (465 μmol) 2-Phenylpropansäurechlorid und 120 mg (930 μmol) DEEA 23.0 mg (57.4 μmol; 62% d. Th.) Pro¬ dukt erhalten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using the general Working Procedures A to D are subsequently admixed with 165.5 mg (930 μmol) of 1-benzothien-2-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 78.1 mg (465 μmol) of 2-phenylpropanoic acid chloride and 120 mg of ( 930 μmol) of DEEA 23.0 mg (57.4 μmol, 62% of theory) of product.
LC-MS (Methode 3): R1 = 2.16 minLC-MS (Method 3): R 1 = 2.16 min
MS (ESI pos): m/z = 401 [M+H]+ MS (ESI pos): m / z = 401 [M + H] +
1H-NMR (400 MHz, DMSO-d6): δ = 1.42 (d, 3H), 3.87 (q, IH), 7.22-7.28 (m, IH), 7.31-7.43 (m, 6H), 7.45-7.56 (m, 3H), 7.70-7.77 (m, 2H), 7.82 (d, IH), 7.90 (s, IH), 7.95 (d, IH), 10.32 (s, IH). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 1.42 (d, 3H), 3.87 (q, IH), 7.22-7.28 (m, IH), 7.31-7.43 (m, 6H), 7.45- 7.56 (m, 3H), 7.70-7.77 (m, 2H), 7.82 (d, IH), 7.90 (s, IH), 7.95 (d, IH), 10.32 (s, IH).
Durch präparative HPLC an chiraler Phase [DAD-Detektion; Säule: KBD 5326(basierend auf Poly(N-methacryloyl-L-leucin-dicyclopropylmethylamid)), 250 mm x 30 mm; Eluent: Es- sigsäureethylester; Fluss: 40 ml/min; Ofen: 240C; UV-Detektion: 254 nm] werden die Enantiomere getrennt.By preparative HPLC on a chiral phase [DAD detection; Column: KBD 5326 (based on poly (N-methacryloyl-L-leucine dicyclopropylmethylamide)), 250 mm x 30 mm; Eluent: ethyl acetate; Flow: 40 ml / min; Oven: 24 ° C; UV detection: 254 nm], the enantiomers are separated.
Analytische HPLC [DAD-Detektion; Säule: KBD 5326 (basierend auf Poly(N-methacryloyl-L- leucin-dicyclopropylmethylamid)), 250 mm x 4.6 mm; Eluent: Essigsäureethylester; Fluss: 2 ml/min; Ofen: 24°C; UV-Detektion: 270 nm] ergibt folgende Retentionszeiten für die Enanti¬ omere:Analytical HPLC [DAD detection; Column: KBD 5326 (based on poly (N-methacryloyl-L-leucine dicyclopropylmethylamide)), 250 mm x 4.6 mm; Eluent: ethyl acetate; Flow: 2 ml / min; Oven: 24 ° C; UV detection: 270 nm] gives the following retention times for the enantiomers:
(SVEnantiomer 10-1 : R, = 3.94 min.(SVEnantiomer 10-1: R, = 3.94 min.
(RVEnantiomer 10-2: R, = 5.95 min.(RVEnantiomer 10-2: R, = 5.95 min.
Beispiel 11Example 11
2-(l-Benzofuran-2-yl)-5-[(2-phenylpropanoyl)amino]benzamid2- (l-benzofuran-2-yl) -5 - [(2-phenylpropanoyl) amino] benzamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5-nitrobenzoe- säurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeits¬ vorschriften A bis D wird anschließend mit 150.6 mg (930 μmol) l-Benzofuran-2-ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 78.1 mg (465 μmol) 2-Phenyl- propansäurechlorid und 120 mg (930 μmol) DIEA 11.2 mg (29.1 μmol; 31 % d. Th.) Produkt erhal¬ ten. 100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using general working instructions A to D, 150.6 mg (930 μmol) of 1-benzofuran-2-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 78.1 mg (465 μmol) of 2- Phenylpropanoic acid chloride and 120 mg (930 μmol) of DIEA 11.2 mg (29.1 μmol, 31% of theory) of product.
LC-MS (Methode 3): R, = 2.09 minLC-MS (Method 3): R, = 2.09 min
MS (ESI pos): m/z = 385 [M+H]+ MS (ESI pos): m / z = 385 [M + H] +
Beispiel 12Example 12
2-(l -Benzothien-3-yl)-5-[(2-phenylpropanoyl)amino]benzamid2- (1-benzothien-3-yl) -5 - [(2-phenylpropanoyl) amino] benzamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5- nitrobenzoesäurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemei¬ nen Arbeitsvorschriften A bis D wird anschließend mit 165.5 mg (930 μmol) l-Benzothien-3- ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(rriphenylphosphin)palladium(0), 78.1 mg (465 μmol) 2-Phenylpropansäurechlorid und 120 mg (930 μmol) DIEA 17.2 mg (42.9 μmol; 46% d. Th.) Pro¬ dukt erhalten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using the general working instructions A to D, then, 165.5 mg (930 μmol) of 1-benzothien-3-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (rriphenylphosphine) palladium (0), 78.1 mg (465 μmol) of 2 Phenylpropanoic acid chloride and 120 mg (930 μmol) of DIEA 17.2 mg (42.9 μmol, 46% of theory) of product.
LC-MS (Methode 3): Rt = 2.08 minLC-MS (Method 3): R t = 2.08 min
MS (ESI pos): m/z = 401 [M+Hf Beispiel 13MS (ESI pos): m / z = 401 [M + Hf Example 13
2-(l,3-Benzodioxol-5-yl)-5-[(2-phenylpropanoyl)amino]benzamid2- (l, 3-benzodioxol-5-yl) -5 - [(2-phenylpropanoyl) amino] benzamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5-nitrobenzoe- säurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeits¬ vorschriften A bis D wird anschließend mit 154.4 mg (930 μmol) l,3-Benzodioxol-5-ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)-palladium(0), 78.1 mg (465 μmol) 2-Phenyl- propansäurechlorid und 120 mg (930 μmol) DIEA 1.9 mg (4.9 μmol; 5% d. Th.) Produkt erhalten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using general working instructions A to D, 154.4 mg (930 μmol) of 1,3-benzodioxol-5-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 78.1 mg (465 μmol ) 2-phenylpropanoic acid chloride and 120 mg (930 μmol) of DIEA 1.9 mg (4.9 μmol, 5% of theory) of product.
LC-MS (Methode 3): R4 = 1.96 minLC-MS (Method 3): R 4 = 1.96 min
MS (ESI pos): m/z = 389 [M+H]+ MS (ESI pos): m / z = 389 [M + H] +
Beispiel 14Example 14
4-[(2-Phenylpropanoyl)amino]-l , 1 ':4', 1 "-terphenyl-2-carboxamid4 - [(2-phenyl-propanoyl) -amino] -l, 1 ': 4', 1 "-terphenyl-2-carboxamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5- nitrobenzoesäurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemei¬ nen Arbeitsvorschriften A bis D wird anschließend mit 184.1 mg (930 μmol) Biphenyl-4- ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 78.1 mg (465 μmol) 2-Phenylpropansäurechlorid und 120 mg (930 μmol) DIEA 26.4 mg (62.8 μmol; 68% d. Th.) Pro¬ dukt erhalten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using the general working instructions A to D, then 184.1 mg (930 μmol) of biphenyl-4-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 78.1 mg (465 μmol) are added. 2-phenylpropanoic acid chloride and 120 mg (930 μmol) of DIEA 26.4 mg (62.8 μmol, 68% of theory) of product.
LC-MS (Methode 3): R, = 2.20 minLC-MS (Method 3): R, = 2.20 min
MS (ESI pos): m/z = 421 [M+H]+ MS (ESI pos): m / z = 421 [M + H] +
1H-NMR (400 MHz, DMSOd6): δ = 1.43 (d, 3H), 3.87 (q, IH), 5.76 (s, 2H), 7.22-7.38 (m, IH), 7.31-7.43 (m, 7H)5 7.44-7.50 (m, 4H), 7.56-7.77 (m, 7H), 10.26 (s, IH). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 1.43 (d, 3H), 3.87 (q, IH), 5.76 (s, 2H), 7.22-7.38 (m, IH), 7.31-7.43 (m, 7H) 5 7.44-7.50 (m, 4H), 7.56-7.77 (m, 7H), 10.26 (s, IH).
Beispiel 15Example 15
3'-Fluor-4-[(2-phenylpropanoyl)amino]- 1 , l':4', 1 "-terphenyl-2-carboxamid3'-Fluoro-4 - [(2-phenylpropanoyl) amino] -1, 1 ': 4', 1 "-terphenyl-2-carboxamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5-nitrobenzoe- säurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeits- vorschriften A bis D wird anschließend mit 201.0 mg (930 μmol) (2-Fluorbiphenyl-4- yl)boronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)-palladium(0), 78.1 mg (465 μmol) 2-Phenylpropansäurechlorid und 120 mg (930 μmol) DIEA 8.0 mg (18.2 μmol; 20% d. Th.) Pro- dukt erhalten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using general operating instructions A to D, then 201.0 mg (930 μmol) (2-fluorobiphenyl-4-yl) boronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 78.1 mg (465 μmol) 2-phenylpropanoic acid chloride and 120 mg (930 μmol) of DIEA 8.0 mg (18.2 μmol, 20% of theory) of product.
LC-MS (Methode 3): Rt = 2.20 minLC-MS (Method 3): R t = 2.20 min
MS (ESI pos): m/z = 439 [M+H]+ Beispiel 16MS (ESI pos): m / z = 439 [M + H] + Example 16
2-(l-Benzothien-2-yl)-5-[(2-benzylbutanoyl)amino]benzamid2- (l-benzothien-2-yl) -5 - [(2-benzylbutanoyl) amino] benzamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5-nitrobenzoe- säurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeits¬ vorschriften A bis D wird anschließend mit 165.5 mg (930 μmol) l-Benzothien-2-ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 91.1 mg (465 μmol) 2-Benzyl- buttersäurechlorid und 120 mg (930 μmol) DIEA 12.1 mg (28.2 μmol; 30% d. Th.) Produkt erhal¬ ten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using general working instructions A to D, then, 165.5 mg (930 μmol) of 1-benzothien-2-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 91.1 mg (465 μmol) of 2 Benzylbutyric acid chloride and 120 mg (930 μmol) of DIEA 12.1 mg (28.2 μmol, 30% of theory) of product were obtained.
LC-MS (Methode 3): R1 = 2.18 minLC-MS (Method 3): R 1 = 2.18 min
MS (ESI pos): m/z = 429 [M+H]+ MS (ESI pos): m / z = 429 [M + H] +
Beispiel 17Example 17
2-(l-Benzothien-3-yl)-5-[(2-benzylbutanoyl)amino]benzamid2- (l-benzothien-3-yl) -5 - [(2-benzylbutanoyl) amino] benzamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5- nitrobenzoesäurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemei¬ nen Arbeitsvorschriften A bis D wird anschließend mit 165.5 mg (930 μmol) l-Benzothien-3- ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 91.1 mg (465 μmol) 2-Benzylbuttersäurechlorid und 120 mg (930 μmol) DlEA 13.6 mg (31.7 μmol; 34% d. Th.) Pro¬ dukt erhalten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using the general working instructions A to D, then, 165.5 mg (930 μmol) of 1-benzothien-3-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 91.1 mg (465 μmol) are used. 2-Benzylbutyric acid chloride and 120 mg (930 μmol) of DlEA 13.6 mg (31.7 μmol, 34% of theory) of product.
LC-MS (Methode 3): R, = 2.17 minLC-MS (Method 3): R, = 2.17 min
MS (ESI pos): m/z = 429 [M+H]+ MS (ESI pos): m / z = 429 [M + H] +
S Beispiel 18S Example 18
2-(l,3-Benzodioxol-5-yl)-5-[(2-benzylbutanoyl)amino]benzamid2- (l, 3-benzodioxol-5-yl) -5 - [(2-benzylbutanoyl) amino] benzamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5-nitrobenzoe- säurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeits- 0 vorschrifiten A bis D wird anschließend mit 154.4 mg (930 μmol) l,3-Benzodioxol-5-ylboronsäure, 10.7 mg (9.3 μmol) Tetτakis(triphenylphosphin)-palladium(0), 91.1 mg (465 μmol) 2-Benzyl- buttersäurechlorid und 120 mg (930 μmol) DIEA 14.9 mg (35.8 μmol; 38% d. Th.) Produkt erhal¬ ten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using general protocols A to D, 154.4 mg (930 μmol) of 1,3-benzodioxol-5-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 91.1 mg (465 μmol) 2-benzyl butyric acid chloride and 120 mg (930 μmol) of DIEA 14.9 mg (35.8 μmol, 38% of theory) of product were obtained.
LC-MS (Methode 3): Rj = 2.02 minLC-MS (Method 3): Rj = 2.02 min
5 MS (ESI pos): m/z = 417 [M+H]+ 5 MS (ESI pos): m / z = 417 [M + H] +
Beispiel 19Example 19
4-[(2-Benzylbutanoyl)amino]- 1 , l':4', 1 "-terphenyl-2-carboxamid4 - [(2-Benzylbutanoyl) amino] -1, 1 ': 4', 1 "-terphenyl-2-carboxamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5-nitrobenzoe- säurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeits¬ vorschriften A bis D wird anschließend mit 184.1 mg (930 μmol) Biphenyl-4-ylboronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 91.1 mg (465 μmol) 2-Benzyl- buttersäurechlorid und 120 mg (930 μmol) DIEA 4.8 mg (10.7 μmol; 12% d. Th.) Produkt erhal¬ ten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using general working instructions A to D, 184.1 mg (930 μmol) of biphenyl-4-ylboronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 91.1 mg (465 μmol) of 2-benzyl- butyric acid chloride and 120 mg (930 μmol) of DIEA 4.8 mg (10.7 μmol, 12% of theory) of product were obtained.
LC-MS (Methode 3): R1 = 2.28 minLC-MS (Method 3): R 1 = 2.28 min
MS (ESI pos): m/z = 449 [M+H]+ MS (ESI pos): m / z = 449 [M + H] +
Beispiel 20Example 20
4-[(2-Benzylbutanoyl)amino]-3 '-fluor- 1 , 1' :4', 1 "-terphenyl-2-carboxamid4 - [(2-Benzylbutanoyl) amino] -3 'fluoro-1, 1': 4 ', 1 "-terphenyl-2-carboxamide
100 mg (93 μmol) entschütztes Rinkamid wird mit 54.5 mg (186 μmol) 2-Iod-5-nitrobenzoe- säurechlorid zu Polymer 1 (Beispiel 6A) umgesetzt. Unter Verwendung der allgemeinen Arbeits¬ vorschriften A bis D wird anschließend mit 200.9 mg (930 μmol) (2-Fluorbiphenyl-4- yl)boronsäure, 10.7 mg (9.3 μmol) Tetrakis(triphenylphosphin)-palladium(0), 91.1 mg (465 μmol) 2-Benzylbuttersäurechlorid und 120 mg (930 μmol) DIEA das Produkt erhalten.100 mg (93 μmol) of deprotected Rinkamide is reacted with 54.5 mg (186 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1 (Example 6A). Using the general working instructions A to D, 200.9 mg (930 μmol) (2-fluorobiphenyl-4- yl) boronic acid, 10.7 mg (9.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 91.1 mg (465 μmol) of 2-benzylbutyric acid chloride and 120 mg (930 μmol) of DIEA the product.
LC-MS (Methode 5): R4 = 1.26 minLC-MS (method 5): R 4 = 1.26 min
MS (ESI pos): m/z = 467 [M+H]+ MS (ESI pos): m / z = 467 [M + H] +
Beispiel 21Example 21
2-( 1 -Benzothien-2-y l)-5- { [2-(4-chlorpheny l)-3 -methylbutanoy 1] amino } benzamid2- (1-benzothien-2-yl) -5- {[2- (4-chlorophenyl) -3-methylbutano] 1] amino} benzamide
Die Herstellung erfolgt analog zur Synthese der Verbindung aus Beispiel 1 aus den entsprechenden Ausgangsverbindungen.The preparation is analogous to the synthesis of the compound from Example 1 from the corresponding starting compounds.
LC-MS (Methode 6): R, = 4.62 min.LC-MS (Method 6): R, = 4.62 min.
MS (DCI): m/z = 463.1 [M+NHjfMS (DCI): m / z = 463.1 [M + NHjf
1H-NMR (400 MHz, DMSO-d6): δ = 0.68 (d, 3H), 1.03 (d, 3H), 2.24-2.41 (m, IH), 3.17 (d, IH), 7.30-7.56 (m, 9H)5 7.68-7.73 (m, 2H), 7.82 (dd, IH), 7.88-7.98 (m, 2H), 10.41 (s, IH). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 0.68 (d, 3H), 1.03 (d, 3H), 2.24-2.41 (m, IH), 3.17 (d, IH), 7.30-7.56 ( m, 9H) 5 7.68-7.73 (m, 2H), 7.82 (dd, IH), 7.88-7.98 (m, 2H), 10.41 (s, IH).
Beispiel 22Example 22
5-[(2-Benzylbutanoyl)amino]-2-chinolin-6-ylbenzamid5 - [(2-Benzylbutanoyl) amino] -2-quinolin-6-ylbenzamide
250 mg (193 μmol) Fmoc-Rinkamid (0.77 mmol/g, Rapp Polymere) wird mit 112.8 mg (385 μmol) 2-Iod-5-nitrobenzoesäurechlorid zu Polymer 1 umgesetzt. Unter Verwendung der allgemeinen Arbeitsvorschrifiten A bis D wird anschließend mit 333.9 mg (1.93 mmol) Chinolin-6- ylboronsäure, 22.3 mg (19.3 μmol) Tetrakis(triphenylphosphin)palladium(0), 175.6 mg (965 μmol) 2-Phenylbuttersäurechlorid und 249 mg (1.93 mmol) DIEA 26.0 mg (64.0 μmol; 32% d. Th.) Pro¬ dukt erhalten. 250 mg (193 μmol) of Fmoc-Rinkamide (0.77 mmol / g, Rapp Polymere) is reacted with 112.8 mg (385 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1. Using general procedures A to D, then 333.9 mg (1.93 mmol) of quinolin-6-ylboronic acid, 22.3 mg (19.3 μmol) of tetrakis (triphenylphosphine) palladium (0), 175.6 mg (965 μmol) of 2-phenylbutyryl chloride and 249 mg (1.93 mmol) DIEA 26.0 mg (64.0 μmol, 32% of theory) product.
LC-MS (Methode 4): R1 = 1.85 minLC-MS (Method 4): R 1 = 1.85 min
MS (ESI pos): m/z = 410 [M+H]+ MS (ESI pos): m / z = 410 [M + H] +
1H-NMR (400 MHz, CDCl3): 8.70-7.00 (m, 14H), 6.10 (d, 2H), 3.50 (t, IH), 2.30-1.80 (m, 2H), 0.90 (t, 3H). 1 H-NMR (400 MHz, CDCl 3): 8.70-7.00 (m, 14H), 6.10 (d, 2H), 3:50 (t, IH), 2.30-1.80 (m, 2H), 0.90 (t, 3H) ,
Beispiel 23Example 23
2-(7-Methoxy-2-naphthyl)-5-[(2-phenylbutanoyl)amino]benzamid2- (7-methoxy-2-naphthyl) -5 - [(2-phenylbutanoyl) amino] benzamide
50 mg (0.12 mmol) der Verbindung aus Beispiel 5A werden mit 37 mg (0.18 mmol) 6-Methoxy- naphthalin-2-boronsäure analog zur Synthese von Beispiel 1 umgesetzt. Man erhält 27 mg (44% d. Th.) Produkt.50 mg (0.12 mmol) of the compound from Example 5A are reacted with 37 mg (0.18 mmol) of 6-methoxynaphthalene-2-boronic acid analogously to the synthesis of Example 1. 27 mg (44% of theory) of product are obtained.
HPLC (Methode 7): R1 = 4.64 minHPLC (Method 7): R 1 = 4.64 min
MS (DCI pos): m/z = 456.3 [M+NRtfMS (DCI pos): m / z = 456.3 [M + NRtf
1H-NMR (400 MHz, DMSO-d6): δ = 0.98 (t, 3H), 1.73 und 2.03-2.16 (mc und m, AB-Signal, 2H), 3.59 (dd, IH), 3.88 (s, 3H), 7.17 (dd, IH), 7.22-7.28 (m, IH), 7.28-7.37 (m, 4H), 7.38-7.45 (m, 3H), 7.48 (dd, IH), 7.64 (s, IH), 7.73-7.76 (m, 2H), 7.76-7.83 (m, 3H), 10.28 (s, IH). Beispiel 24 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 0.98 (t, 3H), 1.73 and 2.03-2.16 (m c and m, AB signal, 2H), 3.59 (dd, IH), 3.88 ( s, 3H), 7.17 (dd, IH), 7.22-7.28 (m, IH), 7.28-7.37 (m, 4H), 7.38-7.45 (m, 3H), 7.48 (dd, IH), 7.64 (s, IH), 7.73-7.76 (m, 2H), 7.76-7.83 (m, 3H), 10.28 (s, IH). Example 24
2-( 1 -Naphthyl)-5-[(2-phenylbutanoyl)amino]benzamid2- (1-naphthyl) -5 - [(2-phenylbutanoyl) amino] benzamide
500 mg (386 μmol) Fmoc-Rinkamid (0.77 mmol/g, Rapp Polymere) wird mit 225.6 mg (770 μmol) 2-Iod-5-nitrobenzoesäurechlorid zu Polymer 1 umgesetzt. Unter Verwendung der allgemeinen Arbeitsvorschriften A bis D wird anschließend mit 664.0 mg (3.86 mmol) 1-Naphthylboronsäure, 44.6 mg (38.6 μmol) Tetrakis(triphenylphosphin)palladium(0), 351.2 mg (1.93 mmol) 2-Phenyl- buttersäurechlorid und 498 mg (3.86 mmol) DIEA 60.0 mg (147.1 μmol; 29% d. Th.) Produkt er¬ halten.500 mg (386 μmol) of Fmoc-Rinkamide (0.77 mmol / g, Rapp Polymere) is reacted with 225.6 mg (770 μmol) of 2-iodo-5-nitrobenzoic acid chloride to give polymer 1. Using general procedure A to D, then 664.0 mg (3.86 mmol) of 1-naphthylboronic acid, 44.6 mg (38.6 μmol) of tetrakis (triphenylphosphine) palladium (0), 351.2 mg (1.93 mmol) of 2-phenylbutyryl chloride and 498 mg (3.86 mmol) DIEA 60.0 mg (147.1 μmol, 29% of theory) product obtained.
LC-MS (Methode 2): R1 = 2.52 minLC-MS (Method 2): R 1 = 2.52 min
MS (ESI pos): m/z = 409 [M+H]+ MS (ESI pos): m / z = 409 [M + H] +
1H-NMR (400 MHz, CDCl3): 8.20-7.20 (m, 14H), 5.20 (s, 2H), 3.45 (t, IH), 2.40-1.80 (m, 2H), 0.95 (t, 3H). 1 H-NMR (400 MHz, CDCl 3 ): 8.20-7.20 (m, 14H), 5.20 (s, 2H), 3.45 (t, IH), 2.40-1.80 (m, 2H), 0.95 (t, 3H) ,
Beispiel 25Example 25
2-(l-Benzothien-2-yl)-5-{[2-(lH-l,254-triazol-5-ylthio)butanόyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (lH-l, 2 5 4-triazol-5-ylthio) butanόyl] amino} benzamide
2-(l-Benzothien-2-yl)-5-[(2-brombutanoyl)amino]benzamid (Beispiel 9A; 50 mg) wird in DMF (1 ml) vorgelegt und mit 3-Mercapto-l,2,4-triazin (15 mg) und Cäsiumcarbonat (78 mg) versetzt und über Nacht bei RT gerührt. Das Reaktionsgemisch wird mit Ethylacetat (50 ml) und 0.5N Salzsäu- re (50 ml) versetzt, die wässrige Phase wird mit Ethylacetat ( zweimal 50 ml) extrahiert, und die vereinigten organischen Phasen werden mit gesättigter Natriumchlorid-Lösung (zweimal 100 ml) gewaschen. Die organische Phase wird über Magnesiumsulfat getrocknet und einrotiert. Der Rück¬ stand wird auf der präparativen HPLC aufgereinigt. Man erhält 14 mg (26% d. Th.) der Titelver¬ bindung.2- (1-Benzothien-2-yl) -5 - [(2-bromobutanoyl) amino] benzamide (Example 9A; 50 mg) is initially charged in DMF (1 ml) and treated with 3-mercapto-l, 2,4- triazine (15 mg) and cesium carbonate (78 mg) and stirred at RT overnight. Ethyl acetate (50 ml) and 0.5N hydrochloric acid (50 ml) are added to the reaction mixture, the aqueous phase is extracted with ethyl acetate (twice 50 ml) and the combined organic phases are washed with saturated sodium chloride solution (twice 100 ml). washed. The organic phase is dried over magnesium sulfate and concentrated by rotary evaporation. The residue is purified on preparative HPLC. 14 mg (26% of theory) of the title compound are obtained.
LC-MS (Methode 6): R1 = 1.79 minLC-MS (Method 6): R 1 = 1.79 min
!+ ! +
MS (ESI): m/z = 438 [M+H]MS (ESI): m / z = 438 [M + H]
1H-NMR (400 MHz, DMSOd6): δ = 10.6 (s, IH), 8.55 (s, IH), 7.95-7.36 (m, 10H), 4.32 (t, IH)3 1.96 (m, 2H), 1.02 (t, 3H) 1 H-NMR (400 MHz, DMSOd 6 ): δ = 10.6 (s, IH), 8.55 (s, IH), 7.95-7.36 (m, 10H), 4.32 (t, IH) 3 1.96 (m, 2H) , 1.02 (t, 3H)
Beispiel 26Example 26
2-(l-Benzothien-2-yl)-5-{[2-(l,3-thiazol-2-yl)butanoyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (l, 3-thiazol-2-yl) butanoyl] amino} benzamide
Natrium-2-(2-thiazolyl)propionat (148 mg) wird in DMF (5 ml) vorgelegt, und mit 2-(l- Benzothien-2-yl)-5-[(2-brombutanoyl)amino]benzamid (Beispiel 8A; 171 mg), HATU (291 mg) und 4-Methylmorpholin (194 mg) versetzt. Das Reaktionsgemisch wird bei RT über Nacht nachge- rührt. Das Reaktionsgemisch wird eingeengt, und der Rückstand wird mittels präparativer HPLC aufgereinigt. Es werden 101 mg (36% d. Th.) Produkt isoliert.Sodium 2- (2-thiazolyl) propionate (148 mg) is initially charged in DMF (5 ml) and treated with 2- (1-benzothien-2-yl) -5 - [(2-bromobutanoyl) amino] benzamide (Example 8A, 171 mg), HATU (291 mg) and 4-methylmorpholine (194 mg). The reaction mixture is stirred at RT overnight. The reaction mixture is concentrated and the residue is purified by preparative HPLC. 101 mg (36% of theory) of product are isolated.
LC-MS (Methode 6): R1 = 2.01 minLC-MS (Method 6): R 1 = 2.01 min
MS (ESI): m/z = 422 [M+H]+ MS (ESI): m / z = 422 [M + H] +
1H-NMR (400 MHz, DMSOd6): δ = 10.7 (s, IH), 7.95-7.36 (m, 1 IH), 4.19 (t, IH), 2.1-1.94 (m, 2H), 0.94 (t, 3H). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 10.7 (s, IH), 7.95-7.36 (m, 1HH), 4.19 (t, IH), 2.1-1.94 (m, 2H), 0.94 (t , 3H).
Beispiel 27Example 27
5-{[2-(3-Fluoφhenyl)butanoyl]amino}-2-chinolin-3-ylbenzamid5 - {[2- (3-Fluoφhenyl) butanoyl] amino} -2-quinolin-3-ylbenzamide
Die Verbindung wird aus Chinolin-3-boronsäure und 2-Iod-5-[(2-(3-fluorphenyl)butanoyl)amino]- benzamid in 13.7 mg (23% d. Th.) Ausbeute in Analogie zu Beispiel 1 hergestellt. The compound is prepared from quinoline-3-boronic acid and 2-iodo-5 - [(2- (3-fluorophenyl) butanoyl) amino] benzamide in 13.7 mg (23% of theory) yield in analogy to Example 1.
2-Iod-5-[(2-(3-fluorphenyl)butanoyl)amino]benzamid wird aus 5-Amino-2-iodbenzamid und 2-(3- Fluorphenyl)butansäure unter Standard-Amidkupplungsbedingungen mit HATU hergestellt.2-iodo-5 - [(2- (3-fluorophenyl) butanoyl) amino] benzamide is prepared from 5-amino-2-iodobenzamide and 2- (3-fluorophenyl) butanoic acid under standard amide coupling conditions with HATU.
LC-MS (Methode 4): R4 = 2.08 minLC-MS (Method 4): R 4 = 2.08 min
MS (ESI): m/z = 428 [M+H]+ MS (ESI): m / z = 428 [M + H] +
1H-NMR (400 MHz, DMSO-d6): δ = 10.32 (s, IH), 7.83-6.68 (m, 14H), 5.05 (d, IH), 3.58 (t, IH), 2.07-1.72 (m, 2H), 0.88 (t, 3H) 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.32 (s, IH), 7.83-6.68 (m, 14H), 5.05 (d, IH), 3.58 (t, IH), 2.07-1.72 ( m, 2H), 0.88 (t, 3H)
Beispiel 28Example 28
2-( 1 -Benzothien-2-yl)-5-[(2-pyridin-3 -ylbutanoy l)amino]benzamid2- (1-benzothien-2-yl) -5 - [(2-pyridin-3-yl-butylbutanoyl) amino] benzamide
Die Titelverbindung wird aus 5-Amino-2-(l-benzothien-2-yl)benzamid und 2-(3-Pyridyl)- propionsäure synthetisiert in Analogie zu Beispiel 26. Man erhält 6.8 mg (8% d. Th.) der Titelver- bindung.The title compound is synthesized from 5-amino-2- (1-benzothien-2-yl) benzamide and 2- (3-pyridyl) propionic acid in analogy to Example 26. 6.8 mg (8% of theory) of Title link.
LC-MS (Methode 4): R, = 1.73 min.LC-MS (Method 4): R, = 1.73 min.
1H-NMR (400 MHz, DMSO-d6): δ = 10.78 (s, IH), 8.88 (s, IH), 8.75 (s, IH), 8.40 (s, IH), 7.87- 7.04 (m, 1 IH), 3.95 (m, IH), 2.16-1.84 (m, 2H), 0.91 (t, 3H). Beispiel 29 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.78 (s, IH), 8.88 (s, IH), 8.75 (s, IH), 8.40 (s, IH), 7.87-7.04 (m, 1 IH), 3.95 (m, IH), 2.16-1.84 (m, 2H), 0.91 (t, 3H). Example 29
4- { [2-(2-Thienyl)butanoyl]amino} -1 , l':4', 1 "-terphenyl-2-carboxamid4- {[2- (2-Thienyl) butanoyl] amino} -1, 1 ': 4', 1 "-terphenyl-2-carboxamide
Die Verbindung wird aus 4-Amino-l,r:4',l"-terphenyl-2-carboxamid und 2-(2-Thienyl)- Propionsäure in 26% Ausbeute in Analogie zu Beispiel 1 hergestellt.The compound is prepared from 4-amino-1, r: 4 ', l "-terphenyl-2-carboxamide and 2- (2-thienyl) - propionic acid in 26% yield in analogy to Example 1.
4-Amino-l,r:4',rι-terphenyl-2-carboxamid wird in Analogie zu der Herstellung von 5-Amino-2-(l- benzothien-2-yl)benzamid (Beispiel 7A und 8A) hergestellt.4-Amino-1, r: 4 ', r ι -terphenyl-2-carboxamide is prepared in analogy to the preparation of 5-amino-2- (1-benzothien-2-yl) benzamide (Example 7A and 8A).
LC-MS (Methode 2): R4 = 2.73 min.LC-MS (Method 2): R 4 = 2.73 min.
HPLC (Methode 1): R4 = 4.64 min.HPLC (Method 1): R 4 = 4.64 min.
MS (ESI pos): m/z = 441 [M+H]+ MS (ESI pos): m / z = 441 [M + H] +
1H-NMR (400 MHz, DMSOd6): δ = 10.39 (s, IH), 7.73-6.98 (m, 17H)5 3.93 (m, IH), 2.06-1.78 (m, 2H), 0.91 (t, 3H). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 10.39 (s, IH), 7.73-6.98 (m, 17H) 5 3.93 (m, IH), 2.06-1.78 (m, 2H), 0.91 (t, 3H).
Beispiel 30Example 30
2-(l-Benzothien-2-yl)-5-{[2-(3-fluorphenyl)butanoyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (3-fluorophenyl) butanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 43.1 mg (51% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 43.1 mg (51% of theory) of the title compound are obtained.
LC-MS (Methode 2): R, = 2.65 min.LC-MS (Method 2): R, = 2.65 min.
HPLC (Methode 1 ): R4 = 4.66 min.HPLC (Method 1): R 4 = 4.66 min.
MS (DCI): m/z = 450 [M+NH,]*MS (DCI): m / z = 450 [M + NH,] *
1H-NMR (400 MHz, DMSO-d6): δ = 10.40 (s, IH), 7.95-7.10 (m, 14H), 3.64 (m, IH), 2.07-1.74 (m, 2H), 0.88 (t, 3H). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.40 (s, IH), 7.95-7.10 (m, 14H), 3.64 (m, IH), 2.07-1.74 (m, 2H), 0.88 ( t, 3H).
Das Racemat wird in die Enantiomere getrennt.The racemate is separated into the enantiomers.
Enantiomer 30-1:Enantiomer 30-1:
R4 = 3.22 min.R 4 = 3.22 min.
Enantiomer 30-2:Enantiomer 30-2:
Rt = 3.78 min.R t = 3.78 min.
Beispiel 31Example 31
2-( 1 -Benzofuran-2-y l)-5- { [2-(2-thieny l)butanoy 1] amino } benzamid 2- (1-benzofuran-2-yl) -5- {[2- (2-thienyl) butano] 1] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 23.4 mg (24% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 23.4 mg (24% of theory) of the title compound are obtained.
LC-MS (Methode 2): R4 = 2.52 min.LC-MS (Method 2): R 4 = 2.52 min.
HPLC (Methode 1): R1 = 4.45 min.HPLC (Method 1): R 1 = 4.45 min.
MS (ESI pos): m/z = 405 [M+H]+ MS (ESI pos): m / z = 405 [M + H] +
1H-NMR (400 MHz, DMSOd6): δ = 10.48 (s, IH), 7.96-6.98 (m, 13H), 3.93 (m, IH), 2.05-1.78 (m, 2H), 0.91 (t, 3H). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 10.48 (s, IH), 7.96-6.98 (m, 13H), 3.93 (m, IH), 2.05-1.78 (m, 2H), 0.91 (t, 3H).
Beispiel 32Example 32
2-(l-Benzothien-2-yl)-5-{[2-(2-furyl)butanoyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (2-furyl) butanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 34.0 mg (47% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 34.0 mg (47% of theory) of the title compound are obtained.
LC-MS (Methode 4): R, = 2.35 min.LC-MS (Method 4): R, = 2.35 min.
HPLC (Methode 1): R, = 4.40 min.HPLC (Method 1): R, = 4.40 min.
MS (ESI pos): m/z = 405 [M+H]+ MS (ESI pos): m / z = 405 [M + H] +
1H-NMR (400 MHz, DMSO-d6): δ = 10.43 (s, IH), 7.95-7.36 (m, HH), 6.41-6.28 (m, 2H)3 3.74 (m, IH), 1.97-1.87 (m, 2H), 0.92 (t, 3H). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.43 (s, IH), 7.95-7.36 (m, HH), 6.41-6.28 (m, 2H) 3 3.74 (m, IH), 1.97- 1.87 (m, 2H), 0.92 (t, 3H).
Beispiel 33Example 33
2-(l-Benzothien-2-yl)-5-{[2-(3-thienyl)butanoyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (3-thienyl) butanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 38.0 mg (48% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 38.0 mg (48% of theory) of the title compound are obtained.
LC-MS (Methode 4): R, = 2.47 min.LC-MS (Method 4): R, = 2.47 min.
HPLC (Methode 1): R4 = 4.46 min.HPLC (Method 1): R 4 = 4.46 min.
MS (DCI): m/z = 438 [M+NH4]+ MS (DCI): m / z = 438 [M + NH4] +
1H-NMR (400 MHz, DMSOd6): δ = 10.35 (s, IH), 7.95-7.14 (m, 13H), 3.71 (m, IH), 2.04-1.75 (m, 2H), 0.89 (t, 3H). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 10.35 (s, IH), 7.95-7.14 (m, 13H), 3.71 (m, IH), 2.04-1.75 (m, 2H), 0.89 (t, 3H).
Beispiel 34Example 34
2-(l-Benzothien-2-yl)-5-{[2-(4-hydroxyphenyl)butanoyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (4-hydroxyphenyl) butanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 23.7 mg (98% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 23.7 mg (98% of theory) of the title compound are obtained.
LC-MS (Methode 4): Rt = 2.19 min.LC-MS (Method 4): R t = 2.19 min.
HPLC (Methode 1): R, = 4.27 min.HPLC (Method 1): R, = 4.27 min.
MS (ESI pos): m/z = 430 [M+H]+ MS (ESI pos): m / z = 430 [M + H] +
1H-NMR (400 MHz, DMSO-d6): δ = 10.26 (s, IH), 9.28 (s, IH), 7.94-6.71 (m, 14H), 3.46 (m, IH), 2.01-1.65 (m, 2H), 0.86 (t, 3H). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.26 (s, IH), 9.28 (s, IH), 7.94-6.71 (m, 14H), 3.46 (m, IH), 2.01-1.65 ( m, 2H), 0.86 (t, 3H).
Beispiel 35Example 35
2-(l-Benzothien-2-yl)-5-{[2-(2,3-dihydro-l,4-benzodioxin-6-yl)butanoyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (2,3-dihydro-l, 4-benzodioxin-6-yl) butanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 15.0 mg (17% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 15.0 mg (17% of theory) of the title compound are obtained.
LC-MS (Methode 6): R4 = 2.25 min.LC-MS (Method 6): R 4 = 2.25 min.
HPLC (Methode 1): R, = 4.63 min.HPLC (Method 1): R, = 4.63 min.
MS (DCI): m/z = 490 PVB-NH4J+ MS (DCI): m / z = 490 PVB-NH 4 J +
1H-NMR (400 MHz, DMSO-d6): δ = 10.29 (s, IH), 7.96-6.81 (m, 13H), 4.21 (m, 4H), 3.46 (m, IH), 2.01-1.66 (m, 2H), 0.86 (t, 3H). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.29 (s, IH), 7.96-6.81 (m, 13H), 4.21 (m, 4H), 3.46 (m, IH), 2.01-1.66 ( m, 2H), 0.86 (t, 3H).
Beispiel 36Example 36
2-( 1 -Benzothien-2-yl)-5- { [2-(4-fluorpheny l)propanoyl] amino } benzamid 2- (1-benzothien-2-yl) -5- {[2- (4-fluorophenyl) -propanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 100,2 mg (64% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 100.2 mg (64% of theory) of the title compound are obtained.
LC-MS (Methode 6): R1 = 2.24 min.LC-MS (Method 6): R 1 = 2.24 min.
HPLC (Methode 1): R4 = 4.55 min.HPLC (Method 1): R 4 = 4.55 min.
MS (DCI): m/z = 436 [M+NHtfMS (DCI): m / z = 436 [M + NH t f
1H-NMR (400 MHz, DMSOd6): δ = 10.34 (s, IH), 7.95-7.17 (m, 14H), 3.87 (q, IH), 1.43 (d, 3H). 1 H NMR (400 MHz, DMSOd 6 ): δ = 10.34 (s, IH), 7.95-7.17 (m, 14H), 3.87 (q, IH), 1.43 (d, 3H).
Beispiel 37Example 37
2-(l-Benzothien-2-yl)-5-{[2-(4-fluorphenyl)butanoyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (4-fluorophenyl) butanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 50.3 mg (62% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 50.3 mg (62% of theory) of the title compound are obtained.
LC-MS (Methode 2): R1 = 2.64 min.LC-MS (method 2): R 1 = 2.64 min.
HPLC (Methode 1): R, = 4.64 min.HPLC (Method 1): R, = 4.64 min.
MS (DCI): m/z = 450 [M+NH,]*MS (DCI): m / z = 450 [M + NH,] *
1H-NMR (400 MHz, DMSO-d6): δ = 10.37 (s, IH), 7.95-7.17 (m, 14H), 3.61 (m, IH), 2.06-1.71 (m, 2H), 0.87 (t, 3H). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.37 (s, IH), 7.95-7.17 (m, 14H), 3.61 (m, IH), 2.06-1.71 (m, 2H), 0.87 ( t, 3H).
Durch Enantiomerentrennung erhält man 8 mg Enantiomer 37-2 aus 20 mg Racemat.Enantiomer separation gives 8 mg of enantiomer 37-2 from 20 mg of racemate.
Beispiel 38Example 38
2-(l-Benzothien-2-yl)-5-{[2-(6-chlorpyridin-3-yl)propanoyl]amino}benzamid 2- (l-benzothien-2-yl) -5 - {[2- (6-chloropyridin-3-yl) propanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 126.8 mg (76% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. This gives 126.8 mg (76% of theory) of the title compound.
LC-MS (Methode 4): R1 = 2.24 min.LC-MS (Method 4): R 1 = 2.24 min.
HPLC (Methode 1): Rt = 4.27 min.HPLC (Method 1): R t = 4.27 min.
MS (DCI): m/z = 453 [M+NH,]"1" MS (DCI): m / z = 453 [M + NH,] "1"
Beispiel 39Example 39
2-(l-Benzothien-5-yl)-5-[(2-phenylbutanoyl)amino]benzamid2- (l-benzothien-5-yl) -5 - [(2-phenylbutanoyl) amino] benzamide
Die Verbindung wird in Analogie zu Beispiel 1 aus Benzothiophen-5-boronsäure hergestellt. Man erhält 44.2 mg (87% d. Th.) der Titelverbindung. The compound is prepared in analogy to Example 1 from benzothiophene-5-boronic acid. 44.2 mg (87% of theory) of the title compound are obtained.
LC-MS (Methode 4): Rt = 2.32 min.LC-MS (Method 4): R t = 2.32 min.
HPLC (Methode 1): R1 = 4.68 min.HPLC (method 1): R 1 = 4.68 min.
MS (DCI): m/z = 432 [M+NH,]+ MS (DCI): m / z = 432 [M + NH,] +
1H-NMR (400 MHz, DMSOd6): δ = 10.35 (s, IH), 7.94-7.25 (m, 15H), 3.60 (m, IH), 2.08-1.72 (m, 2H), 0.88 (t, 3H). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 10.35 (s, IH), 7.94-7.25 (m, 15H), 3.60 (m, IH), 2.08-1.72 (m, 2H), 0.88 (t, 3H).
Durch Enantiomerentrennung erhält man 77 mg Enantiomer 39-2 aus 160 mg Racemat.Enantiomer separation gives 77 mg enantiomer 39-2 from 160 mg racemate.
Enantiomer 39-2:Enantiomer 39-2:
R, = 5.61 min.R, = 5.61 min.
Beispiel 40Example 40
2-( 1 -Benzothien-2-y l)-5- { [2-(4-cyanophenyl)butanoyl] amino } benzamid2- (1-benzothien-2-yl) -5- {[2- (4-cyanophenyl) butanoyl] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 22.4 mg (27% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. 22.4 mg (27% of theory) of the title compound are obtained.
LC-MS (Methode 2): R1 = 2.50 min. HPLC (Methode 1): R4 = 4.66 min.LC-MS (Method 2): R 1 = 2.50 min. HPLC (Method 1): R 4 = 4.66 min.
MS (ESI pos): m/z = 440 [M+H]+ MS (ESI pos): m / z = 440 [M + H] +
1H-NMR (400 MHz, DMSO-d6): δ = 10.45 (s, IH), 7.94-7.36 (m, 14H), 3.72 (m, IH), 2.09-1.75 (m, 2H), 0.89 (t, 3H). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, IH), 7.94-7.36 (m, 14H), 3.72 (m, IH), 2.09-1.75 (m, 2H), 0.89 ( t, 3H).
Beispiel 41Example 41
2-( 1 -Benzothien-2-yl)-5- { [2-(2-thieny l)butanoy l]amino } benzamid2- (1-benzothien-2-yl) -5- {[2- (2-thienyl) butanoylo] amino} benzamide
Die Verbindung wird in Analogie zu Beispiel 26 hergestellt. Man erhält 12.0 mg (15% d. Th.) der Titelverbindung.The compound is prepared in analogy to Example 26. This gives 12.0 mg (15% of theory) of the title compound.
LC-MS (Methode 4): R1 = 2.46 min.LC-MS (Method 4): R 1 = 2.46 min.
1H-NMR (400 MHz, DMSOd6): δ = 10.46 (s, IH), 7.95-6.98 (m, 13H), 3.93 (m, IH), 2.05-1.78 (m, 2H), 0.91 (t, 3H). 1 H-NMR (400 MHz, DMSOd 6 ): δ = 10.46 (s, IH), 7.95-6.98 (m, 13H), 3.93 (m, IH), 2.05-1.78 (m, 2H), 0.91 (t, 3H).
Das Racemat wird in die Enantiomere getrennt.The racemate is separated into the enantiomers.
Enantiomer 41-1:Enantiomer 41-1:
Rt = 3.84 min.R t = 3.84 min.
Enantiomer 41-2:Enantiomer 41-2:
R1 = 5.61 min. B) Bewertung der physiologischen WirksamkeitR 1 = 5.61 min. B) Assessment of physiological efficacy
Die Eignung der erfindungsgemäßen Verbindungen zur Behandlung von Herz-Kreislauf- Erkrankungen kann in folgenden Assay-Systemen gezeigt werden:The suitability of the compounds according to the invention for the treatment of cardiovascular diseases can be demonstrated in the following assay systems:
Funktioneller Reporter Assay für das Hochdurchsatzscreening von IL8B Rezeptor Antago- nistenFunctional reporter assay for high throughput screening of IL8B receptor antagonists
CHO Zellen mit mitochondrial lokalisiertem Aequorin werden stabil transfϊziert mit dem humanen IL8B Rezeptor und dem G-alpha-16 Protein. Aktivierung des IL8B Rezeptors mit IL8 oder eines endogenen P2Y Rezeptors mit ATP führt zu einer Ca2+ Freisetzung. Dieser intrazelluläre Ca2+ Transient kann mit mitochondrial lokalisiertem Aequorin biolumineszent detektiert werden. IL8 induzierte Ca2+ Transienten werden durch IL8B Rezeptor Antagonisten inhibiert. Substanzen, die auch ATP-induzierte Ca2+ Transienten inhibieren sind unspezifisch.CHO cells with mitochondrially localized aequorin are stably transfected with the human IL8B receptor and the G-alpha-16 protein. Activation of the IL8B receptor with IL8 or an endogenous P2Y receptor with ATP leads to Ca 2+ release. This intracellular Ca 2+ transient can be detected bioluminescently with mitochondrially localized aequorin. IL8-induced Ca 2+ transients are inhibited by IL8B receptor antagonists. Substances that also inhibit ATP-induced Ca 2+ transients are nonspecific.
2000 Zellen in 25 μl Komplettmedium mit 10% FCS pro Loch einer 384er Multititerplatte werden 24h bei 370C und 5% CO2 inkubiert. Nach dem Entfernen des Mediums werden 30μl einer 11.8μM Coelenterazin-Lösung in 2mM Ca-Tyrode zugegeben und die Zellen weitere 4 Stunden bei 37°C in 5% CO2 inkubiert. lOμl Testsubstanz in 2mM Ca-Tyrode/0.1% BSA werden zugege¬ ben und die Zellen 5 Minuten bei Raumtemperatur inkubiert. Der IL8B Rezeptor wird durch die Zugabe von 25μl einer 0.78-2.6nM IL8-Lösung in 2mM Ca-Tyrode/0.1% BSA aktiviert oder der endogene P2Y Rezeptor wird durch die Zugabe von 25 μl einer 7.8-26μM ATP-Lösung in 2mM Ca-Tyrode aktiviert. Die Biolumineszenz wird zeitgleich aufgezeichnet. IC50 Werte werden unter Verwendung des Marquardt-Levenberg-Fit aus Dosis-Wirkungskurven berechnet (Tabelle A).2000 cells in 25 ul complete medium containing 10% FCS per well of a 384-well multititer plate are incubated at 37 0 C and 5% CO 2 for 24 h. After removal of the medium, 30 μl of a 11.8 μM coelenterazine solution in 2 mM Ca-Tyrode are added and the cells are incubated for a further 4 hours at 37 ° C. in 5% CO 2 . 10 μl of test substance in 2 mM Ca-Tyrode / 0.1% BSA are added and the cells are incubated for 5 minutes at room temperature. The IL8B receptor is activated by the addition of 25μl of a 0.78-2.6nM IL8 solution in 2mM Ca-Tyrode / 0.1% BSA or the endogenous P2Y receptor is prepared by adding 25μl of a 7.8-26μM ATP solution in 2mM Ca. Tyrode activated. The bioluminescence is recorded at the same time. IC 50 values are calculated using dose-response curves using the Marquardt-Levenberg-Fit (Table A).
Tabelle A;Table A;
IL-8 induzierter ROS f reactive oxygen species) Assay mit primären humanen PMNLTs IL-8 induced ROS f reactive oxygen species) assay with primary human PMNLTs
Humane PMNL 's werden aus Frischblut freiwilliger Spender isoliert (gemäss Beschreibung in Current Protocols in Immunology, Vol. I, Suppl. 1, Unit 7.23.1). Die isolierten Zellen werden vor ihrem Einsatz in DMEM (Dulbecco's minimal essential medium) bei 4 - 8 0C gelagert.Human PMNLs are isolated from fresh blood volunteer donors (as described in Current Protocols in Immunology, Vol. I, Suppl. 1, Unit 7.23.1). The isolated cells are stored at 4 - 8 ° C. before use in DMEM (Dulbecco's minimal essential medium).
Testsubstanzen, Luminol (50 μM), Horse Radish Peroxidase (HRP; 1 U/ml) und rekombinantes humanes IL-8 (10 - 50 nM) werden mit der PMN Zellsuspension inkubiert und die emmittierte Lumineszenz als RLU's (relative light units) im Luminometer unverzüglich gemessen. Diese gilt als Mass für die IL-8 induzierte ROS Generierung. Die Fläche unter der entsprechenden Kurve wird herangezogen, um die inhibitorische Aktivität und die halb-maximale inhibitorische Konzent- ration der getesteten Substanzen zu bestimmen.Test substances, luminol (50 μM), Horse Radish Peroxidase (HRP; 1 U / ml) and recombinant human IL-8 (10-50 nM) are incubated with the PMN cell suspension and the emitted luminescence as RLU's (relative light units) in the luminometer measured immediately. This is considered a measure of the IL-8 induced ROS generation. The area under the corresponding curve is used to determine the inhibitory activity and the half-maximal inhibitory concentration of the tested substances.
IL8 BindungsaffinitätIL8 binding affinity
Zellkultur: CHO Zellen, die mit dem humanen IL8 Rezeptor B transfiziert worden sind, werden in DMEM Medium mit 10% FCS, Penicillin (100 units/ml), Streptomycin (100 μg/ml) und 0.4 mg/ml G418 kultiviert.Cell culture: CHO cells transfected with the human IL8 receptor B are cultured in DMEM medium with 10% FCS, penicillin (100 units / ml), streptomycin (100 μg / ml) and 0.4 mg / ml G418.
Membranpräparation : Zellen werden subkonfluent mit Trypsin geerntet und bei 500 x g für 5 min abzentrifugiert. Das Zellpellet wird mit PBS gewaschen und danach in eiskaltem Assaypuffer auf¬ genommen (50 mM Tris-HCl, 10 mM EDTA, 10 mM MgCl2, pH 7.4 einschliesslich einmal Pro¬ tease inhibitor Cocktail (#1873580, Roche)). Anschliessend werden die Zellen mit einem Polytron 30 Sekunden auf Eis homogenisiert und für 10 min bei 500 x g bei 4 0C abzentrifugiert, um die Zellkerne zu entfernen. Der Überstand wird dann bei 100000 x g zentrifugiert (30 min, 40C) und das Membranpellet in Assaypuffer resuspendiert. Die Membranpräparation wird bei -800C einge¬ froren und der Proteingehalt mittels des BCA Tests (Pierce) bestimmt.Membrane Preparation: Cells are harvested subconfluently with trypsin and centrifuged at 500 xg for 5 min. The cell pellet is washed with PBS and then taken up in ice-cold assay buffer (50 mM Tris-HCl, 10 mM EDTA, 10 mM MgCl 2 , pH 7.4 including one time protease inhibitor cocktail (# 1873580, Roche)). Subsequently, the cells are homogenized with ice for 30 seconds on a polytron and centrifuged for 10 min at 500 xg at 4 0 C to remove the cell nuclei. The supernatant is then centrifuged at 100,000 xg (30 min, 4 0 C) and the membrane pellet resuspended in assay buffer. The membrane preparation is frozen einge¬ at -80 0 C and the protein content using the BCA assay (Pierce).
Rezeptorbindung: Rezeptormembranen (1 μg) werden mit 0.2 nM 125I markiertem IL8 (Amersham) für 2h in Assaypuffer bei Raumtemperatur in An- und Abwesenheit von Testsubstanz inkubiert. Rezeptorgebundenes EL8 wird durch Zugabe von WGA SPA Beads (Amersham) in einem Wallac Scintillationszähler gemessen.Receptor binding: Receptor membranes (1 μg) are incubated with 0.2 nM 125 I labeled IL8 (Amersham) for 2 h in assay buffer at room temperature in the presence and absence of test substance. Receptor-bound EL8 is measured by adding WGA SPA beads (Amersham) in a Wallac scintillation counter.
IL-8 Peritonitis Modell (in vivo Assay)IL-8 peritonitis model (in vivo assay)
Gemessen wird die IL-8 induzierte Migration von neutrophilen Granulozyten aus dem Blut in dasMeasured is the IL-8-induced migration of neutrophil granulocytes from the blood into the blood
Peritoneum der Maus. Hierzu werden weibliche BALB/c Mäuse (n=6-8) mit humanem rekombi- nantem IL-8 [10ug/kg, 25ml/kg] i.p. injiziert. Zwei Stunden später werden die Tiere abgetötet und die Bauchhöhle zur Gewinnung der eingewanderten Zellen ausgespült. Eingewanderte neutrophile Granulozyten werden mit fluoreszenzmarkierten Antikörpern, die an das Zelloberflächenantigen Ly-6G binden, markiert und mittels FACS quantifiziert.Peritoneum of the mouse. For this purpose, female BALB / c mice (n = 6-8) are injected ip with human recombinant IL-8 [10 μg / kg, 25 ml / kg]. Two hours later, the animals are killed and the abdominal cavity is rinsed to recover the immigrant cells. Immigrated neutrophils Granulocytes are labeled with fluorescently labeled antibodies that bind to the cell surface antigen Ly-6G and quantified by FACS.
Substanzen werden 30 min (p.o.) [10ml/kg] oder 10 min (i.v.) [5ml/kg] vor der EL-8 Stimulation appliziert. Der prozentuale Anteil der Neutrophilen an der Gesamtzellzahl wird für die Placebo behandelte unstimulierte" Kontrollgruppe, die IL-8-stimulierte Kontrollgruppe sowie für die sub¬ stanzbehandelten Tiere ermittelt. Die durch Substanzgabe hervorgerufene prozentuale Hemmung sowie die Signifikanz (t-test) der IL-8 induzierten Neutrophilenmigration berechnet sich relativ zu den IL-8 behandelten Kontrolltieren.Substances are administered 30 min (po) [10 ml / kg] or 10 min (iv) [5 ml / kg] before EL-8 stimulation. The percentage of neutrophils in the total cell number is determined, the IL-8-stimulated control group and for the substances, substance-treated animals for the placebo-treated unstimulated "control group. The induced by administration of substance, the percentage inhibition as well as the significance (t-test) of the IL- 8 induced neutrophil migration is calculated relative to the IL-8 treated control animals.
Atherosklerose Modell in Mäusen (in vivo Assay)Atherosclerosis model in mice (in vivo assay)
Zur Bestimmung der anti-atherosklerotischen Wirkung von IL-8 Rezeptor Antagonisten werden in der Forschung allgemein anerkannte Tiermodelle verwendet, wie die ApoE knockout Maus (Red¬ dick, R.L., et al., Arterioscler. Thromb. 1994, 14, 141-147) oder die LDL-Rezeptor knockout Maus (Ishibashi, S., et al., Proc. Natl. Acad. Sei. USA 1993, 91, 4431-4435). In allen Modellen wird ent¬ weder in Kurzzeituntersuchungen (1-2 Monate) die anti-atherosklerotische Wirkung durch eine veränderte Genexpression von relevanten Markergenen in Atherosklerose-anfalligem Gewebe indi¬ rekt bestimmt, oder in Langzeitunterversuchungen (3-6 Monate) die Entstehung von atherosklero- tischen Plaques mit Hilfe von histologischen Techniken direkt bestimmt.To determine the anti-atherosclerotic effect of IL-8 receptor antagonists, generally accepted animal models are used in research, such as the ApoE knockout mouse (Red¬ dick, RL, et al., Arterioscler, Thromb., 1994, 14, 141-147). or the LDL receptor knockout mouse (Ishibashi, S., et al., Proc Natl Acad., USA 1993, 91, 4431-4435). In all models, neither in short-term examinations (1-2 months) the anti-atherosclerotic effect is indirectly determined by altered gene expression of relevant marker genes in atherosclerosis-susceptible tissue, or in long-term studies (3-6 months) the onset of atherosclerosis - Table plaques determined directly using histological techniques.
HF Modell in der Ratte (in vivo Assav)HF model in the rat (in vivo Assav)
Männliche Wistar Ratten (300 g; Harlan/Winkelmann) werden mit 5% Isofluran narkotisiert, intu- biert und unter 2% Isofluran, Sauerstoff, Lachgas mit einer Beatmungspumpe (ugo basile 7025 rodent; 7 ml/Hub; 50 Hübe pro min) beatmet. Der Brustkorb wird eröffnet und am Herzen wird dieMale Wistar rats (300 g, Harlan / Winkelmann) are anesthetized with 5% isoflurane, intubated and ventilated under 2% isoflurane, oxygen, nitrous oxide with a ventilator pump (ugo basile 7025 rodent, 7 ml / stroke, 50 strokes per min) , The ribcage is opened and at the heart of the
LAD (linke absteigende Koronararterie) mit einem Faden (PROLENE 1 metric 5-0 ETHICONlH) unterstochen und abgebunden. Das Tier wird wieder zugenäht, wundversorgt und die Narkose beendet. Die orale Behandlung mit EL-8 Rezeptor Antagonisten beginnt 1-2 Tage nach der Okklu- sion der LAD.LAD (left descending coronary artery) with a thread (PROLENE 1 metric 5-0 ETHICONlH) undercut and ligated. The animal is sewn up again, wound-fed and the anesthesia ended. Oral treatment with EL-8 receptor antagonists begins 1-2 days after the LAD occlusion.
Über mehrere Wochen oder Monate werden in regelmäßigen Abständen EKG und echokardi- ographische Untersuchungen gemacht, um die Entwicklung einer Herzinsuffizienz, mit und ohne 11-8 Rezeptor Antagonisten, in den Ratten zu analysieren. Blutproben werden regelmäßig abge¬ nommen, um Biomarker (z. B. BNP), die ein klinisch anerkanntes Maß für die Entwicklung von Herzinsiffϊzienz sind, zu bestimmen. Am Ende des Versuchs wird bei den Tieren unter Isofluran- narkose (2% Isofluran, Sauerstoff, Lachgas) die Kontraktilität des Herzen mit einem Miliar Druckkatheter in vivo bestimmt, die Herzen entnommen und histologisch charakterisiert. Weitere HF in vivo Assay-Systeme sind aus der Literatur bekannt: Braun A. et al., Circ. Res., 90, 270-6 (2002); Wang Q.-D. et al., J. Pharmacol. Toxicol. Methods, 50, 163-74 (2004); Monnet E. et al., Ann. Thorac. Surg., 79, 1445-53 (2005); Caligiuriet G. et al, Proc.Natl.Acad.Sci., 96, 6920-4 (1999).Periodic ECG and echocardiographic examinations are performed over several weeks or months to analyze the development of heart failure, with and without 11-8 receptor antagonists, in the rats. Blood samples are taken regularly to determine biomarkers (eg, BNP) that are a clinically accepted measure of the development of cardiac insufficiency. At the end of the experiment, in the animals under isoflurane anesthesia (2% isoflurane, oxygen, nitrous oxide), the contractility of the heart is determined with a milliliter pressure catheter in vivo, the hearts are removed and histologically characterized. Other in vivo in vivo assay systems are known in the literature: Braun A. et al., Circ. Res., 90, 270-6 (2002); Wang Q.-D. et al., J. Pharmacol. Toxicol. Methods, 50, 163-74 (2004); Monnet E. et al., Ann. Thorac. Surg., 79, 1445-53 (2005); Caligiuriet G. et al, Proc. Natl. Acad. Sci., 96, 6920-4 (1999).
C) Ausführungsbeispiele für pharmazeutische ZusammensetzungenC) Exemplary embodiments of pharmaceutical compositions
Die erfindungsgemäßen Substanzen können folgendermaßen in pharmazeutische Zubereitungen überführt werden:The substances according to the invention can be converted into pharmaceutical preparations as follows:
Tablette:Tablet:
Zusammensetzung:Composition:
100 mg der Verbindung des Beispiels 1, 50 mg Lactose (Monohydrat), 50 mg Maisstärke, 10 mg Polyvinylpyrolidon (PVP 25) (Fa. BASF, Deutschland) und 2 mg Magnesiumstearat.100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Germany) and 2 mg of magnesium stearate.
Tablettengewicht 212 mg. Durchmesser 8 mm, Wölbungsradius 12 mm.Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.
Herstellung:production:
Die Mischung aus der Verbindung des Beispiels 1, Lactose und Stärke wird mit einer 5%-igen Lösung (m/m) des PVPs in Wasser granuliert. Das Granulat wird nach dem Trocknen mit dem Magnesiumstearat für 5 min. gemischt. Diese Mischung wird mit einer üblichen Tablettenpresse verpresst (Format der Tablette siehe oben).The mixture of the compound of Example 1, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules, after drying with the magnesium stearate for 5 min. mixed. This mixture is compressed with a conventional tablet press (for the tablet format see above).
Orale Suspension:Oral suspension:
Zusammensetzung:Composition:
1000 mg der Verbindung des Beispiels 1, 1000 mg Ethanol (96%), 400 mg Rhodigel (Xanthan gum) (Fa. FMC, USA) und 99 g Wasser.1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of rhodigel (xanthan gum) (FMC, USA) and 99 g of water.
Einer Einzeldosis von 100 mg der erfindungsgemäßen Verbindung entsprechen 10 ml orale Sus¬ pension.A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
Herstellung:production:
Das Rhodigel wird in Ethanol suspendiert, die Verbindung des Beispiels 1 wird der Suspension zugefügt. Unter Rühren erfolgt die Zugabe des Wassers. Bis zum Abschluss der Quellung des Rhodigels wird ca. 6h gerührt. Intravenös applizierbare Lösung:The rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels is complete, it is stirred for about 6 hours. Intravenous solution:
Zusammensetzung:Composition:
1 mg der Verbindung von Beispiel 1, 15 g Polyethylenglykol 400 und 250 g Wasser für Injektions¬ zwecke.1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for Injektions¬ purposes.
Herstellung:production:
Die Verbindung von Beispiel 1 wird zusammen mit Polyethylenglykol 400 in dem Wasser unter Rühren gelöst. Die Lösung wird sterilfiltriert (Porendurchmesser 0.22 μm) und unter aseptischen Bedingungen in hitzesterilisierte Infusionsflaschen abgefüllt. Diese werden mit Infusionsstopfen und Bördelkappen verschlossen. The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile-filtered (pore diameter 0.22 μm) and filled under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

Claims

Patentansprüche claims
1. Verbindung der Formel1. Compound of the formula
in welcherin which
Y für eine Bindung, Methandiyl, Schwefel oder Sauerstoff steht,Y is a bond, methanediyl, sulfur or oxygen,
R1 für Biphenyl-4-yl steht, wobei in Biphenyl-4-yl 1 bis 3 Kohlenstoffatome durch Stickstoff ersetzt sein können,R 1 is biphenyl-4-yl, where in biphenyl-4-yl 1 to 3 carbon atoms may be replaced by nitrogen,
oderor
für l,3-Benzodioxol-5-yl oder 2,3-Dihydro-l,4-benzodioxin-5-yl steht,is l, 3-benzodioxol-5-yl or 2,3-dihydro-l, 4-benzodioxin-5-yl,
oderor
für eine Gruppe der Formelfor a group of the formula
steht,stands,
wobeiin which
X für N, O oder S steht,X is N, O or S,
* die Anknüpfstelle an das Kohlenstoffatom ist, und der Phenylring über die 4 oder 5 Position gebunden ist, wenn der Fünfring über die 2-Position an das Kohlenstoffatom gebunden ist, oder der Phenyl¬ ring über die 5 Position gebunden ist, wenn der Fünfring über die 3- Position an das Kohlenstoffatom gebunden ist,* is the point of attachment to the carbon atom, and the phenyl ring is attached via the 4 or 5 position when the five-membered ring is bonded to the carbon atom via the 2-position, or the phenyl ring is bonded through the 5-position when the five-membered ring is bonded to the carbon atom via the 3-position .
oderor
Naphth-1-yl oder Naphth-2-yl steht, wobei in Naphth-1-yl und Naphth-2-yl 1 Koh¬ lenstoffatom durch Stickstoff ersetzt sein kann,Naphth-1-yl or naphth-2-yl, in which naphth-1-yl and naphth-2-yl 1 Koh¬ lenstoffatom may be replaced by nitrogen,
oderor
für eine Gruppe der Formelfor a group of the formula
steht,stands,
wobeiin which
W für C oder N steht,W is C or N,
V für N, O oder S steht,V is N, O or S,
* die Anknüpfstelle an das Kohlenstoffatom ist, und* is the point of attachment to the carbon atom, and
die Gruppe über die 2, 3, 5 oder 6 Position an das Kohlenstoffatom gebun¬ den ist,the group is bonded to the carbon atom via the 2, 3, 5 or 6 position,
oderor
für eine Gruppe der Formelfor a group of the formula
steht, wobeistands, in which
U für N, O oder S steht,U stands for N, O or S,
* die Anknüpfstelle an das Kohlenstoffatom ist, und* is the point of attachment to the carbon atom, and
die Gruppe über die 2, 3, 5 oder 6 Position an das Kohlenstoffatom gebun- den ist,the group is attached to the carbon atom via the 2, 3, 5 or 6 position,
wobei die Reste R1 substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe beste¬ hend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Q- Cβ-Alkyl, Ci-Cό-Alkoxy, Ci-C6-Alkylamino, Hydroxycarbonyl, Ci-C6- Alkoxycarbonyl, Aminocarbonyl, Ci-Cβ-Alkylaminocarbonyl, Ci-C6-where the radicals R 1 may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group beste¬ starting from hydroxy, amino, halo, cyano, trifluoromethyl, trifluoromethoxy, Q- Cβ alkyl, Ci-C ό Alkoxy, C 1 -C 6 -alkylamino, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -
Alkylcarbonyl und Ci-Cβ-Alkylcarbonylamino,Alkylcarbonyl and C 1 -C 6 -alkylcarbonylamino,
R2 für Wasserstoff, CrC6-Alkyl oder C3-C7-Cycloalkyl steht,R 2 is hydrogen, C r C 6 alkyl or C 3 -C 7 cycloalkyl,
R3 für C3-C7-Cycloalkyl oder gegebenenfalls mit bis zu fünf Fluor substituiertes Ci-C4-Alkyl steht,R 3 is C 3 -C 7 -cycloalkyl or optionally substituted by up to five fluorine-substituted C 1 -C 4 -alkyl,
R7 für eine Gruppe der FormelR 7 is a group of the formula
steht,stands,
wobeiin which
* die Anknüpfstelle an Y ist,* is the link to Y,
R4, R5 und R6 unabhängig voneinander für Wasserstoff, Hydroxy, Ami¬ no, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Ci-C6- Alkyl, Ci-Ce-Alkoxy, CrC6-Alkylamino, C3-C7-Cycloalkyl, 5- bis 7-gliedriges Heterocyclyl, C6-Ci0-Aryl, 5- oder 6-gliedriges Hete- roaryl, Hydroxycarbonyl, Ci-C6-Alkoxycarbonyl, Aminocarbonyl, CrCö-Alkylaminocarbonyl, Ci-C6-Alkylcarbonyl oder Ci-Cß- Alkylcarbonylamino steht,R 4, R 5 and R 6 are independently hydrogen, hydroxy, Ami¬ no, halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C 6 - alkyl, Ci-Ce-alkoxy, C r C 6 alkylamino, C 3 - C 7 -cycloalkyl, 5- to 7-membered heterocyclyl, C 6 -C 0 aryl, 5- or 6-membered hetero- roaryl, hydroxycarbonyl, Ci-C 6 alkoxycarbonyl, aminocarbonyl, -C ö alkylaminocarbonyl, Ci-C 6 alkylcarbonyl or C ß - alkylcarbonylamino group,
worin Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten un¬ abhängig voneinander ausgewählt werden aus der Gruppe beste¬ hend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, C1-Ce-AIlCyI, Ci-Cö-Alkoxy, Ci-C6-Alkylamino, Hydroxycarbonyl, Ci-C6-Alkoxycarbonyl, Aminocarbonyl, Ci-Cg- Alkylaminocarbonyl, Ci-Cö-Alkylcarbonyl und Ci-C6- Alkylcarbonylamino,in which cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 AIlCyI, Ci-COE-alkoxy, Ci-C 6 -alkylamino, hydroxycarbonyl, Ci-C 6 alkoxycarbonyl, aminocarbonyl, Ci-Cg-alkylaminocarbonyl, Ci-C ö alkylcarbonyl and Ci-C 6 - alkylcarbonylamino,
oderor
R und R5 an benachbarte Kohlenstoffatome gebunden sind und eine -0-CH2-CH2-O- Brücke bilden,R and R 5 are attached to adjacent carbon atoms and form a -O-CH 2 -CH 2 -O- bridge,
oderor
für ein 5- oder 6-gliedriges Heteroaryl steht,represents a 5- or 6-membered heteroaryl,
worin Heteroaryl substituiert sein kann mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Ci-Cό-Alkyl, Ci-Cβ-Alkoxy und Ci-C6-Alkylamino,wherein heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C ό -alkyl, Ci-Cβ-alkoxy and ci C 6 alkylamino,
oder eines ihrer Salze, ihrer Solvate oder der Solvate ihrer Salze.or one of its salts, its solvates or the solvates of its salts.
Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass sie der FormelCompound according to claim 1, characterized in that it has the formula
entspricht, in welcher Y für eine Bindung oder Methandiyl steht,corresponds, in which Y is a bond or methanediyl,
R1 für Biphenyl-4-yl, l,3-Benzodioxol-5-yl, 2,3-Dihydro-l,4-benzodioxin-5-yl, 5-Phe- nyl-thien-2-yl, 5-Phenyl-furan-2-yl, Naphth-1-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2-yl, l-Benzothien-3-yl, l-Benzothien-5-yl, l-Benzothien-6-yl, l-Benzofuran-2-yl oder l-Benzofuran-3-yl steht,R 1 is biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenyl-thien-2-yl, 5-phenyl -furan-2-yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1 Benzothien-6-yl, 1-benzofuran-2-yl or 1-benzofuran-3-yl,
wobei Biphenyl-4-yl, l,3-Benzodioxol-5-yl, 2,3-Dihydro-l,4-benzodioxin-5-yl, 5-Phenyl-thien-2-yl, 5-Phenyl-furan-2-yl, Naphth-1-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2-yl, l-Benzothien-3-yl, l-Benzothien-5-yl, l-Benzothien-6-yl, l-Benzofuran-2-yl und l-Benzofuran-3-yl substituiert sein können mit 1 bis 3 Sub- stituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Ci-Cβ-Alkyl, Ci-C6-Alkoxy, Ci-Cβ-Alkylamino, Hydroxycarbo- nyl, Cj-Cβ-Alkoxycarbonyl, Aminocarbonyl, Ci-Cö-Alkylaminocarbonyl, Ci-C6- Alkylcarbonyl und Ci-Ce-Alkylcarbonylamino,wherein biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenyl-thien-2-yl, 5-phenyl-furan-2 -yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1-benzothien-6 -yl, 1-benzofuran-2-yl and 1-benzofuran-3-yl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl , Trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl and C 1 -C 4 alkylcarbonylamino,
R2 für Wasserstoff oder CrC6-Alkyl steht,R 2 is 6 alkyl, hydrogen or C r C,
R3 für C3-C7-Cycloalkyl oder gegebenenfalls mit bis zu fünf Fluor substituiertes CrC4-Alkyl steht,R 3 is C 3 -C 7 -cycloalkyl or optionally substituted by up to five fluorine-substituted C r C 4 -alkyl,
R4, R5 und R6 unabhängig voneinander für Wasserstoff, Hydroxy, Amino, Halogen, Cya¬ no, Trifluormethyl, Trifluormethoxy, Ci-Cβ-Alkyl, Ci-Cβ-Alkoxy, Ci-Cβ- Alkylamino, C3-C7-Cycloalkyl, 5- bis 7-gliedriges Heterocyclyl, C6-Ci0-Aryl, 5- oder 6-gliedriges Heteroaryl, Hydroxycarbonyl, CrCö-Alkoxycarbonyl, Aminocar¬ bonyl, Ci-Ce-Alkylaminocarbonyl, Ci-C6-Alkylcarbonyl oder Ci-C6- Alkylcarbonylamino steht,R 4 , R 5 and R 6 independently of one another represent hydrogen, hydroxyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 3 -C 7 Cycloalkyl, 5- to 7-membered heterocyclyl, C 6 -C 10 -aryl, 5- or 6-membered heteroaryl, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl or Ci-C 6 - alkylcarbonylamino,
worin Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluor¬ methyl, Trifluormethoxy, Ci-C6-Alkyl, CrC6-Alkoxy, Ci-Cö-Alkylamino, Hydro¬ xycarbonyl, Ci-Cβ-Alkoxycarbonyl, Aminocarbonyl, Ci-Cβ-Alkylaminocarbonyl, Ci-Cβ-Alkylcarbonyl und Ci-Cβ-Alkylcarbonylamino.in which cycloalkyl, heterocyclyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C r C 6 alkoxy, Ci-C ö alkylamino, Hydro¬ xycarbonyl, Ci-Cβ-alkoxycarbonyl, aminocarbonyl, Ci-Cβ-alkylaminocarbonyl, Ci-Cβ-alkylcarbonyl and Ci-Cβ-alkylcarbonylamino.
Verbindung nach Anspruch 2, dadurch gekennzeichnet, dassConnection according to claim 2, characterized in that
Y für eine Bindung oder Methandiyl steht, R1 für Biphenyl-4-yl, l,3-Benzodioxol-5-yl, 2,3-Dihydro-l,4-benzodioxin-5-yl, 5-Phe- nyl-thien-2-yl, 5-Phenyl-furan-2-yl, Naphth-1-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2-yl, l-Benzothien-3-yl, l-Benzothien-5-yl, l-Benzothien-6-yl, l-Benzofuran-2-yl oder l-Benzofuran-3-yl steht,Y is a bond or methanediyl, R 1 is biphenyl-4-yl, l, 3-benzodioxol-5-yl, 2,3-dihydro-l, 4-benzodioxin-5-yl, 5-phenyl-thien-2-yl, 5-phenyl -furan-2-yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothien-3-yl, 1-benzothien-5-yl, 1 Benzothien-6-yl, 1-benzofuran-2-yl or 1-benzofuran-3-yl,
wobei Biphenyl-4-yl, l,3-Benzodioxol-5-yl, wherein biphenyl-4-yl, l, 3-benzodioxol-5-yl,
2,2,
3-Dihydro-l,4-benzodioxin-5-yl,3-dihydro-l, 4-benzodioxin-5-yl,
5-Phenyl-thien-2-yl, 5-Phenyl-furan-2-yl, Naphth-1-yl, Naphth-2-yl, Chinolin-6-yl, l-Benzothien-2-yl, l-Benzothien-3-yl, l-Benzothien-5-yl, l-Benzothien-6-yl, l-Benzofuran-2-yl und l-Benzofuran-3-yl substituiert sein können mit 1 bis 3 Sub- stituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl,5-phenyl-thien-2-yl, 5-phenyl-furan-2-yl, naphth-1-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl, 1-benzothienyl 3-yl, 1-benzothien-5-yl, 1-benzothien-6-yl, 1-benzofuran-2-yl and 1-benzofuran-3-yl may be substituted with 1 to 3 substituents, the substituents being independently are selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl,
Trifluormethoxy, Ci-Cö-Alkyl, Ci-C6-Alkoxy, Ci-C6-Alkylamino, Hydroxycarbo- nyl, CpC6-Alkoxycarbonyl, Aminocarbonyl, Ci-Cö-Alkylaminocarbonyl, CpC6- Alkylcarbonyl und Ci-Cβ-Alkylcarbonylamino,Trifluoromethoxy, Ci-C ö alkyl, Ci-C 6 alkoxy, Ci-C 6 -alkylamino, Hydroxycarbo- nyl, CpC 6 alkoxycarbonyl, aminocarbonyl, Ci-C ö alkylaminocarbonyl, CpC 6 - alkylcarbonyl and Ci-Cβ- alkylcarbonylamino,
R2 für Wasserstoff oder C1-C6-AIlCyI steht,R 2 is hydrogen or C 1 -C 6 -alkyl,
R3 für C3-C7-Cycloalkyl oder gegebenenfalls mit bis zu fünf Fluor substituiertesR 3 is C 3 -C 7 cycloalkyl or optionally substituted with up to five fluorine
Ci-C4-Alkyl steht,Ci-C 4 -alkyl,
R4, R5 und R6 unabhängig voneinander für Wasserstoff, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, CrQ-Alkyl, C3-C7-Cycloalkyl, Hydroxycarbonyl, C1-C6- Alkoxycarbonyl, Aminocarbonyl, Ci-Cö-Alkylaminocarbonyl, Ci-C6-Alkylcarbonyl oder Ci-Co-Alkylcarbonylamino steht,R 4, R 5 and R 6 are independently hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, CRQ alkyl, C 3 -C 7 cycloalkyl, hydroxycarbonyl, C 1 -C 6 - alkoxycarbonyl, aminocarbonyl, Ci-C ö - Alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl or C 1 -C -alkylcarbonylamino,
worin Cycloalkyl substituiert sein kann mit 1 bis 3 Substituenten, wobei die Sub¬ stituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, C1-C6- Alkyl, Ci-Cό-Alkoxy, CpCβ-Alkylamino, Hydroxycarbonyl, Cj-C6-Alkoxycarb- onyl, Aminocarbonyl, CpCδ-Alkylaminocarbonyl, Cj-Cö-Alkylcarbonyl und Ci-C6-wherein cycloalkyl may be substituted with 1 to 3 substituents, wherein the substances, substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 - alkyl, Ci-C ό - alkoxy, CpCβ-alkylamino, hydroxycarbonyl, Cj-C 6 -Alkoxycarb- onyl, aminocarbonyl, CpC δ alkylaminocarbonyl, Cj-C ö alkylcarbonyl and Ci-C 6 -
Alkylcarbonylamino.Alkylcarbonylamino.
4. Verbindung nach einem der Ansprüche 2 oder 3, dadurch gekennzeichnet, dass4. A compound according to any one of claims 2 or 3, characterized in that
Y für eine Bindung oder Methandiyl steht,Y is a bond or methanediyl,
R1 für Biphenyl-4-yl, 5-Phenyl-thien-2-yl, Naphth-2-yl, Chinolin-6-yl, 1-Benzothien- 2-yl oder l-Benzofuran-2-yl, wobei Biphenyl-4-yl und Naphth-2-yl substituiert sein können mit 1 bis 2 Substi- tuenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Fluor, Chlor, Methoxy und Ethoxy,R 1 is biphenyl-4-yl, 5-phenylthien-2-yl, naphth-2-yl, quinolin-6-yl, 1-benzothien-2-yl or 1-benzofuran-2-yl, where biphenyl-4-yl and naphth-2-yl may be substituted by 1 to 2 substituents, the substituents being selected independently of one another from the group consisting of fluorine, chlorine, methoxy and ethoxy,
R2 für Wasserstoff steht,R 2 is hydrogen,
R3 für Methyl, Ethyl oder Isopropyl steht,R 3 is methyl, ethyl or isopropyl,
R4, R5 und R6 unabhängig voneinander für Wasserstoff oder Halogen stehen.R 4 , R 5 and R 6 are independently hydrogen or halogen.
5. Verfahren zur Herstellung einer Verbindung der Formel (Ia) nach Anspruch 1, dadurch gekennzeichnet, dass5. A process for preparing a compound of formula (Ia) according to claim 1, characterized in that
[A] eine Verbindung der Formel[A] a compound of the formula
in welcherin which
Y, R2, R3 und R7 die in Anspruch 1 angegebene Bedeutung haben,Y, R 2 , R 3 and R 7 have the meaning given in claim 1,
mit einer Verbindung der Formelwith a compound of the formula
^B(OH)2 R1/ 2 (JE),^ B (OH) 2 R 1/2 (JE),
in welcherin which
R1 die in Anspruch 1 angegebene Bedeutung hat,R 1 has the meaning given in claim 1,
oderor
[B] eine Verbindung der Formel [B] a compound of the formula
in welcherin which
R1 und R2 die in Anspruch 1 angegebene Bedeutung haben,R 1 and R 2 have the meaning given in claim 1,
mit einer Verbindung der Formelwith a compound of the formula
in welcherin which
Y, R3 und R7 die in Anspruch 1 angegebene Bedeutung haben, undY, R 3 and R 7 have the meaning given in claim 1, and
X1 für Halogen, bevorzugt Iod oder Brom, oder Hydroxy steht,X 1 is halogen, preferably iodine or bromine, or hydroxy,
umgesetzt wird.is implemented.
6. Verbindung nach einem der Ansprüche 1 bis 4 zur Behandlung und/oder Prophylaxe von Krankheiten.6. A compound according to any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases.
7. Arzneimittel enthaltend mindestens eine Verbindung nach einem der Ansprüche 1 bis 4 in Kombination mit mindestens einem inerten, nichttoxischen, pharmazeutisch geeigneten Hilfsstoff.7. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4 in combination with at least one inert, non-toxic, pharmaceutically suitable excipient.
8. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 4 zur Herstellung eines Arzneimittels.8. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament.
9. Arzneimittel nach Anspruch 7 zur Behandlung und/oder Prophylaxe von inflammatori¬ schen Erkrankungen.9. Medicament according to claim 7 for the treatment and / or prophylaxis of inflammatory disorders.
10. Verfahren zur Bekämpfung von Arteriosklerose in Menschen und Tieren durch Verab- reichung einer wirksamen Menge mindestens einer Verbindung nach einem der Ansprüche10. A method for combating arteriosclerosis in humans and animals by administering an effective amount of at least one compound according to any one of the claims
1 bis 4 oder eines Arzneimittels nach Anspruch 7 oder 9. 1 to 4 or a medicament according to claim 7 or 9.
11. Interleukin-8 Rezeptor Antagonisten zur Behandlung und/oder Prophylaxe von Herzinsuf¬ fizienz.11. Interleukin-8 receptor antagonists for the treatment and / or prophylaxis of cardiac insufficiency.
12. Verwendung eines Interleukin-8 Rezeptor Antagonisten zur Herstellung eines Arzneimit¬ tels zur Behandlung und/oder Prophylaxe von Herzinsuffizienz. 12. Use of an interleukin-8 receptor antagonist for the production of a medicament for the treatment and / or prophylaxis of cardiac insufficiency.
EP05813330A 2004-11-20 2005-11-17 Substituted [(phenylethanoyl)amino] benzamides and the use thereof in the treatment of inflammatory and cardio-vascular diseases Withdrawn EP1814872A1 (en)

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