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EP2197846A1 - Acides 6-phénylnicotiniques substitués et leur utilisation - Google Patents

Acides 6-phénylnicotiniques substitués et leur utilisation

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Publication number
EP2197846A1
EP2197846A1 EP08801700A EP08801700A EP2197846A1 EP 2197846 A1 EP2197846 A1 EP 2197846A1 EP 08801700 A EP08801700 A EP 08801700A EP 08801700 A EP08801700 A EP 08801700A EP 2197846 A1 EP2197846 A1 EP 2197846A1
Authority
EP
European Patent Office
Prior art keywords
mmol
trifluoromethyl
substituted
alkyl
fluorine
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Withdrawn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
EP08801700A
Other languages
German (de)
English (en)
Inventor
Lars BÄRFACKER
Barbara ALBRECHT-KÜPPER
Peter Kolkhof
Yolanda Cancho Grande
Adam Nitsche
Heinrich Meier
Carsten Schmeck
Jens Schamberger
Klemens Lustig
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 Intellectual Property GmbH
Original Assignee
Bayer Animal Health GmbH
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 Animal Health GmbH filed Critical Bayer Animal Health GmbH
Publication of EP2197846A1 publication Critical patent/EP2197846A1/fr
Withdrawn legal-status Critical Current

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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Definitions

  • the present application relates to novel substituted 6-phenyl-nicotinic acid derivatives, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, preferably for the treatment and / or prophylaxis Cardiovascular diseases, in particular of dyslipidaemias, atherosclerosis and heart failure.
  • fibrates are currently the only treatment option for patients in these risk groups. They lower elevated triglycerides by 20-50%, lower LDL-C by 10-15%, change the LDL particle size from low density atherogenic LDL to normal dense and less atherogenic LDL and increase the HDL concentration by 10-15%.
  • Fibrates act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) - alpha ⁇ Nature 1990, 347, 645-50).
  • PPAR-alpha is a nuclear receptor that regulates the expression of target genes by binding to DNA sequences in the promoter region of these genes [also called PPAR response elements (PPRE)].
  • PPREs have been identified in a number of genes that encode proteins that regulate lipid metabolism.
  • PPAR-alpha is highly expressed in the liver and its activation leads, inter alia, to decreased VLDL production secretion and reduced apolipoprotein CHI (ApoCHT1 synthesis), in contrast to the synthesis of apolipoprotein Al (ApoAl).
  • a disadvantage of previously approved fibrates is their weak interaction with the receptor (EC 50 in the ⁇ M range), which in turn leads to the relatively low pharmacological effects described above.
  • WO 98/45268 claims nicotinamide derivatives with PDE 4D and TNF-inhibitory activity for the treatment of respiratory diseases as well as allergic, inflammatory and rheumatoid diseases.
  • cyclopentyl-substituted pyridines are described for the treatment of hypertension.
  • Variously substituted 2-arylpyridines as C5a receptor ligands for the treatment of inflammatory, immunological and cardiovascular diseases are disclosed in WO 2004/043925.
  • substituted pyridine derivatives are described as DPP-IV inhibitors for the treatment of diabetes.
  • WO 2005/049573 and WO 2005/049606 describe substituted nicotinic acid esters as synthesis intermediates without biological activity.
  • WO 2006/103120 discloses heterocyclic compounds and their use for the treatment of Alzheimer's disease.
  • substituted pyridines for the treatment of cancer are described in WO 2006/124874.
  • WO 2006/028958 claims 2-arylpyridines for the treatment of tumor diseases.
  • WO 2006/097220 claims 4-phenoxy-2-phenylpyrimidinecarboxylic acids and, in WO 2008/031500 and WO 2008/031501, 4-phenoxy- or 2-phenoxynicotinic acids as PPAR-alpha modulators for the treatment of dyslipidemias and arteriosclerosis.
  • WO 2008/016643 discloses substituted 2- and 4-aminopyridines for the treatment of various diseases.
  • the present invention relates to compounds of the general formula (I)
  • one of the ring members A and D is N and the other is CR 7 ,
  • R 7 is hydrogen, methyl or ethyl
  • R 1 is (C 3 -C 10 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, -NR A R B , -OR C or -SR D , where (C 3 -C 10) -alkyl may be substituted by one or two substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C 1 -C 4 ) -alkoxy, trifluoromethoxy and (C 3 -C 7 ) -cycloalkyl,
  • Trifluoromethyl, 2,2,2-trifluoroethyl, (C r C 4) -alkoxy and trifluoromethoxy may be substituted
  • Trifluoroethyl, (C 1 -C 4 ) -alkoxy and trifluoromethoxy can be substituted
  • R A is hydrogen or (C r C 3 ) -alkyl
  • R B is (C, -C O) -alkyl or (C 3 -C 7) cycloalkyl
  • (C 1 -C 10) -alkyl can be substituted by one substituent selected from the group consisting of hydroxyl, (C 1 -C 4 ) -alkoxy and (C 3 -C 7 ) -cycloalkyl,
  • (C 3 -C 7 ) -cycloalkyl having one or two substituents independently selected from the group fluorine, hydroxy, oxo, (Ci-C 4 ) - alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C r C 4 ) alkoxy and
  • Trifluoromethoxy can be substituted
  • (C 3 -C 7 ) -cycloalkyl having one or two substituents independently of one another is selected from the group consisting of fluorine, hydroxyl, oxo, (C 1 -C 4 ) -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C r C 4 ) Alkoxy and trifluoromethoxy can be substituted,
  • R c and R D are (C 2 -C 10 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, where (C 2 -C 10) -alkyl can be substituted by a substituent selected from the group consisting of hydroxyl, (C 1 -C 4 ) -alkoxy and (C 3 -C 7 ) -cycloalkyl,
  • (C 3 -C 7) cycloalkyl with one or two substituents independently selected from the group fluoro, hydroxy, oxo, (C r C4) alkyl, trifluoromethyl, 2,2,2-trifluoroethyl,
  • (C 3 -C 7 ) -cycloalkyl having one or two substituents independently selected from the group fluorine, hydroxy, oxo, (C 1 -C 4 ) -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C r C 4 ) alkoxy and
  • Trifluoromethoxy can be substituted
  • R 1 is methyl, ethyl, methoxy or methylthio
  • (C 3 -C 7 ) -cycloalkyl having one or two substituents independently selected from the group fluorine, hydroxy, oxo, (C 1 -C 4 ) -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C r C 4 ) alkoxy and trifluoromethoxy can be substituted,
  • R 2 is (C r C 3 ) -alkyl or cyclopropyl
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen, fluorine, chlorine or methyl
  • R 5 is hydrogen, halogen, nitro, cyano, trifluoromethyl, methyl, ethyl, trifluoromethoxy or methoxy
  • R 6 is hydrogen, fluorine, chlorine or methyl
  • R 3 , R 4 , R 5 and R 6 is different from hydrogen
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes 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 used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, 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 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, Triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammoni
  • 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. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but are reacted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • the present invention also includes hydrolyzable ester derivatives of the carboxylic acids of the formula (I).
  • esters which can be hydrolyzed enzymatically or chemically to the free carboxylic acids in physiological media and in particular in vivo.
  • esters straight-chain or branched (C 1 -C 6 ) -alkyl esters in which the alkyl group is hydroxyl, Amino, mono- (C 1 -C 4 ) -alkylamino and / or may be substituted.
  • Particularly preferred are the methyl or ethyl esters of the compounds of formula (I).
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2 Methylbutyl, 3-methylbutyl, n -hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl, 4.4 Dimethylpentyl and 1,4,4-trimethylpentyl.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated alkyl radical having 3 to 7 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 6 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
  • Di-alkylamino in the context of the invention is an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 6 carbon atoms. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino , N-ethyl-Nn-pentylamino and N-n-hexyl-N-methylamino.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • one of the ring members A and D stands for ⁇ and the other stands for CR 7 ,
  • R 7 is hydrogen or methyl
  • R 1 is (C 3 -C 8 ) -alkyl, cyclopropyl, -R A R B or -OR C ,
  • R A is hydrogen or (C r C 3 ) -alkyl
  • R B is (Ci-Cg) -alkyl, cyclopropyl, cyclopentyl or cyclohexyl
  • (C 1 -C 8 ) -alkyl may be substituted by a substituent selected from the group consisting of methoxy, ethoxy, cyclopropyl, cyclopentyl and cyclohexyl,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl, trifluoromethyl and methoxy,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl, trifluoromethyl and methoxy,
  • R c is (C 2 -Cg) -alkyl, cyclopropyl, cyclopentyl or cyclohexyl,
  • (C 2 -Cg) -alkyl can be substituted by a substituent selected from the group consisting of methoxy, ethoxy, cyclopropyl, cyclopentyl and cyclohexyl,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl, trifluoromethyl and methoxy,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl, trifluoromethyl and methoxy,
  • R 1 is methyl, ethyl or methoxy
  • methyl, ethyl and methoxy are each substituted with cyclopropyl, cyclopentyl or cyclohexyl, in which cyclopropyl, cyclopentyl and cyclohexyl can be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl, trifluoromethyl and methoxy,
  • R 2 is ethyl, iso-propyl or trifluoromethyl
  • R 3 is hydrogen
  • R 4 is hydrogen or fluorine
  • R 5 is hydrogen, fluorine, chlorine, trifluoromethyl or methyl
  • R 6 is hydrogen or fluorine
  • one of the ring members A and D is N and the other is CH,
  • R 1 is n-propyl, iso-propyl, n-butyl, iso-butyl, 1-methylpropyl, -NR A R B or -OR C ,
  • R A is hydrogen, methyl or ethyl
  • R B is ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, 1-methylpropyl or cyclopropyl,
  • cyclopropyl may be substituted with a substituent selected from the group fluorine, methyl and trifluoromethyl,
  • R c is n-propyl, iso-propyl, n-butyl, iso-butyl, 1-methylpropyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein cyclopropyl, cyclopentyl and cyclohexyl may be substituted with one substituent selected from the group consisting of fluorine, methyl and trifluoromethyl,
  • R 1 is methoxy or ethoxy
  • methoxy and ethoxy are each substituted with cyclopropyl, cyclopentyl or cyclohexyl,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted with a substituent selected from the group fluorine, methyl and trifluoromethyl,
  • R 2 is ethyl or trifluoromethyl
  • R 3 is hydrogen
  • R 4 is hydrogen or fluorine
  • R 5 is hydrogen, chlorine or methyl
  • R 6 is hydrogen or fluorine
  • one of the ring members A and D is N and the other is CH,
  • R 1 is n-propyl, iso-propyl, n-butyl, iso-butyl, 1-methylpropyl or -OR C ,
  • R c is n-propyl, iso-propyl, n-butyl, iso-butyl, 1-methylpropyl, cyclopropyl, cyclopentyl or cyclohexyl,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted with one substituent selected from the group consisting of fluorine, methyl and trifluoromethyl, or
  • R 1 is methoxy or ethoxy
  • methoxy and ethoxy are each substituted with cyclopropyl, cyclopentyl or cyclohexyl,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted with a substituent selected from the group fluorine, methyl and trifluoromethyl,
  • R 2 is ethyl or trifluoromethyl
  • R 3 is hydrogen
  • R 4 is hydrogen or fluorine
  • R 5 is hydrogen, chlorine or methyl
  • R 6 is hydrogen or fluorine
  • R 2 is trifluoromethyl.
  • R 2 is methyl or ethyl.
  • R 1 is n-propyl, iso-propyl, n-butyl, iso-butyl or 1-methylpropyl.
  • R 1 is (C 3 -C 8 ) -alkyl or -OR C ,
  • (C 3 -C 8 ) -alkyl can be substituted by one or two substituents selected from among fluorine, trifluoromethyl, hydroxy, methoxy, ethoxy and trifluoromethoxy,
  • R c is (C 2 -C 8 ) -alkyl, cyclopropyl, cyclopentyl or cyclohexyl,
  • (C 2 -C 8 ) -alkyl may be substituted by a substituent selected from the group consisting of methoxy, ethoxy, cyclopropyl, cyclopentyl and cyclohexyl,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted with a substituent selected from the group fluorine, methyl, ethyl, trifluoromethyl and methoxy.
  • R 1 is methyl, ethyl or methoxy
  • methyl, ethyl and methoxy are each substituted with cyclopropyl, cyclopentyl or cyclohexyl,
  • cyclopropyl, cyclopentyl and cyclohexyl may be substituted with a substituent selected from the group fluorine, methyl, ethyl, trifluoromethyl and methoxy.
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (II)
  • X 1 is a suitable leaving group such as halogen, in particular chlorine
  • R 8 is (C r C 4 ) -alkyl
  • R 1A is methyl, ethyl, (C 3 -C, 0) alkyl or (C 3 -C 7) cycloalkyl,
  • Trifluoromethoxy and (C 3 -C 7 ) -cycloalkyl may be substituted
  • (C 3 -C 7 ) -cycloalkyl having one or two substituents independently selected from the group fluorine, hydroxy, oxo, (C r C 4 ) alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C r C 4 ) alkoxy and trifluoromethoxy can be substituted,
  • X 2 represents a group of the formula -B (OR 9 ) 2 or -ZnHaI
  • Hal is halogen, in particular chlorine, bromine or iodine
  • R y is hydrogen or (C r C 4 ) alkyl
  • both radicals R 9 together form a -C (CH 3 ) 2 -C (CH 3 ) 2 bridge,
  • R 1B is methoxy, methylthio, -NR A R B , -OR C or -SR D ,
  • (C 3 -C 7 ) -cycloalkyl having one or two substituents independently selected from the group fluorine, hydroxy, oxo, (Q -C 4 ) -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C r C 4 ) alkoxy and trifluoromethoxy can be substituted,
  • R ⁇ , R B , R c and R D have the meanings given above,
  • the compounds of the formulas (HI-A) and (HI-B) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.
  • X 3 represents a suitable leaving group such as, for example, halogen, in particular chlorine, in an inert solvent in the presence of a suitable transition metal catalyst and optionally a base with a compound of formula (VI)
  • R 3 , R 4 , R 5 and R 6 each have the meanings given above, and
  • X 4 represents the group -B (OR 9 ) 2 , -ZnHaI or -MgHaI,
  • R 10 is (C 1 -C 10 -alkyl or benzyl
  • R 1 ' is (C 1 -C 4 ) -alkyl or benzyl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 10 and R 11 each have the meanings given above,
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 11 each have the meanings given above,
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 11 each have the meanings given above, transferred.
  • the compounds of the formula (II) in which A is CR 7A and D is N, in which R 7A is methyl or ethyl, can be prepared by reacting compounds of the formula (X) in which the nitrogen atom is protected Presence of a base with a compound of the formula (XH)
  • X 5 represents a suitable leaving group such as, for example, halogen, in particular bromine or iodine, into a compound of the formula (XHI)
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7A and R 11 are each as defined above,
  • PG is a temporary protecting group, in particular p-methoxybenzyl
  • the invention further provides a process for the preparation of the compounds according to the invention of the formula (I) in which A is CH and D is N, which comprises reacting a compound of the formula (XI) in an inert solvent under Mitsunobu conditions a compound of formula (IH-C)
  • R 1C is methoxy or -OR C ,
  • R 1C , R 2 , R 3 , R 4 , R 5 , R 6 and R 11 each have the meanings given above,
  • R 1C , R 2 , R 3 , R 4 , R 5 and R 6 each have the meanings given above,
  • the compounds of the formulas (HI-C) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.
  • the invention further provides a process for the preparation of the compounds according to the invention of the formula (I) in which A is CR 7 and D is N, which comprises reacting a compound of the formula (XIV)
  • R 1A , R 2 , R 7 and R 8 each have the meanings given above,
  • X 6 represents a suitable leaving group such as, for example, halogen, in particular chlorine,
  • R, 1A, ⁇ R> 2, R 3, RD 4 , DR 5 , DR ' TM and DR' are each as defined above,
  • the compounds of the formula (XTV) can be prepared by reacting compounds of the formula (XV)
  • R 1A , R 2 , R 7 and R 8 have the meanings given above,
  • a suitable oxidizing agent such as 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone
  • a suitable halogenating agent such as phosphorus oxychloride
  • the compounds of the formula (XV) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.
  • Transition metal catalysts, catalyst ligands and auxiliary bases for the coupling reactions are (H) + (mA) ⁇ (IV-A), (V) + (VI) ⁇ (H) and (XIV) + (VI) ⁇ (IV-D) known from the literature [cf. e.g. J. Hassan et al., Chem. Rev. K) 2, 1359-1469 (2002)] and commercially available. Preference is given to using palladium or nickel catalysts.
  • Inert solvents for process step (H) + (HI-B) - »(TV-B) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions , or other solvents such as dimethylformamide, dimethylsulfoxide, NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone ( ⁇ MP), pyridine, acetone, 2-butanone or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using dimethylformamide or tetrahydrofuran.
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene
  • Suitable bases for process step (H) + (HI-B) - »(IV-B) are customary inorganic bases. These include in particular alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal hydrides such as sodium or potassium hydride, or organometallic bases such as n-butyllithium. Preference is given to sodium hydride and n-butyllithium.
  • the base is used here in an amount of 1 to 5 mol, preferably in an amount of 1.2 to 3 mol, based on 1 mol of the compound of formula (IH-B).
  • the reaction (IT) + (IH-B) -> (IV-B) is generally carried out in a temperature range from O 0 C to +150 0 C, preferably at +20 0 C to + 12O 0 C.
  • the reaction can at normal, elevated or at reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.
  • triphenylphosphine or tri-n-butylphosphine, 1, 2-bis (diphenylphosphino) ethane (DPPE), diphenyl (2-pyridyl) phosphine (Ph2P-Py), (p-dimethylaminophenyl ) diphenylphosphine (DAP-DP), tris (4-dimethylaminophenyl) phosphine (tris-DAP) and a suitable dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, NNN'N ' Tetramethylazodicarboxamide (TMAD), 1,1 '- (azodicarbonyl) dipiperidine (ADDP) or 4,7-dimethyl-3,5,7-hexahydro-
  • DPPE 1, 2-bis (diphen
  • Inert solvents for the Mitsunobu reaction (XI) + (HI-C) -> (IV-C) are, for example, ethers such as tetrahydrofuran, diethyl ether, hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane or other solvents such as Acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, THF is used.
  • the Mitsunobu reaction (XI) + (HI-C) -> (FV-C) is generally carried out in a temperature range from -78 ° C to +180 0 C, preferably at 0 0 C to + 50 0 C, optionally in a microwave.
  • the reactions can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar).
  • the alkylation (X) + (XH) - »(Xm) is generally carried out in a temperature range from -78 ° C to + 50 0 C, preferably at -78 ° C to +20 0 C.
  • the reactions can be carried out at normal, elevated or at reduced pressure (eg from 0.5 to 5 bar). In general, you work at normal pressure.
  • Suitable bases for the alkylation (X) + (XFl) -> (XIFl) are customary organic and inorganic bases. These include in particular alkali metal hydrides such as sodium or potassium hydride and amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide or organometallic compounds such as n-butyllithium or phenyllithium. Preference is given to lithium diisopropylamide and lithium bis (trimethylsilyl) amide.
  • Inert solvents for the alkylation (X) + (XU) -> (XHI) are, for example, ethers such as tetrahydrofuran, diethyl ether, hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane or other solvents such as acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, THF is used.
  • Suitable inert solvents for the hydrolysis of the carboxylic acid esters are water or the organic solvents customary for ester cleavage. These include in particular alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, acetonitrile, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
  • Suitable bases for the ester hydrolysis are the customary inorganic bases. These include in particular alkali metal or alkaline earth metal hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Preference is given to using sodium hydroxide or potassium hydroxide.
  • Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
  • Hydrogen chloride or trifluoroacetic acid are preferred in the case of tert-butyl esters and hydrochloric acid in the case of methyl esters.
  • benzyl ester cleavage takes place under hydrogenolytic conditions in an inert solvent in the presence of a suitable catalyst, in particular 10% palladium on carbon.
  • a suitable catalyst in particular 10% palladium on carbon.
  • Ammonium formate can also be used as the hydrogen source.
  • Suitable inert solvents for the hydrogenolysis of the benzyl esters are water or the organic solvents customary for ester cleavage. These include in particular alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, acetonitrile, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
  • the Esterspaltung is generally carried out in a temperature range of 0 0 C to +100 0 C, preferably from 0 0 C to +50 0 C.
  • the reaction may be at atmospheric, elevated or reduced pressure is performed (for example from 0.5 to 5 bar) ,
  • the compounds according to the invention are highly effective PPAR-alpha modulators and moreover have increased metabolic stability. They are particularly useful for primary and / or secondary prevention and treatment of cardiovascular disorders caused by disorders in fatty acid and glucose metabolism.
  • cardiovascular disorders include dyslipidaemias (hypercholesterolemia, hypertriglyceridemia, elevated levels of postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidemias), arteriosclerosis, and metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance , Glucose intolerance, obesity (obesity) and diabetic sequelae such as retinopathy, nephropathy and neuropathy).
  • dyslipidaemias hypercholesterolemia, hypertriglyceridemia, elevated levels of postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidemias
  • arteriosclerosis and metabolic disorders (metabolic syndrome
  • the compounds according to the invention are also particularly suitable for primary and / or secondary prevention and treatment of cardiac insufficiency.
  • cardiac insufficiency also encompasses more specific or related forms of disease such as right heart failure, left heart failure, global insufficiency, hypertension-induced heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, valvular heart failure, valvular heart failure, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis , Tricuspid regurgitation, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure, and systolic heart failure.
  • myocarditis chronic myocarditis, acute myocarditis, viral myocarditis, diabetic
  • CAD-I independent cardiovascular disease risk factors
  • hypertension ischemia, myocardial infarction, angina pectoris, myocardial insufficiency, restenosis, pulmonary hypertension, increased levels of fibrinogen and low density LDL, and elevated levels of plasminogen activator.
  • Inhibitor 1 PAI-I
  • the compounds according to the invention can also be used for the treatment and / or prevention of cancers such as, for example, skin cancer, breast cancer, brain tumors, head Cervical tumors, liposarcomas, carcinomas of the eye, gastrointestinal tract, thyroid, liver, pancreas, respiratory organs, kidney, ureter, prostate, genital tract and their distant metastases, as well as lymphomas, sarcomas and leukemias become.
  • cancers such as, for example, skin cancer, breast cancer, brain tumors, head Cervical tumors, liposarcomas, carcinomas of the eye, gastrointestinal tract, thyroid, liver, pancreas, respiratory organs, kidney, ureter, prostate, genital tract and their distant metastases, as well as lymphomas, sarcomas and leukemias become.
  • the compounds according to the invention can also be used for the treatment and / or prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thromboses, edema, disorders of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease).
  • vasculitis micro- and macrovascular damage
  • reperfusion damage arterial and venous thromboses
  • edema disorders of the central nervous system and neurodegenerative disorders
  • stroke Alzheimer's disease, Parkinson's disease.
  • the activity of the compounds of the invention can be e.g. in vitro by the transactivation assay described in the Examples section.
  • the efficacy of the compounds of the invention in vivo can be e.g. Check by the tests described in the example section.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of dyslipidaemias, arteriosclerosis and heart failure.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • Suitable combination active ingredients are lipid metabolism-altering active ingredients, antidiabetic agents, hypotensive agents, circulation-promoting and / or antithrombotic agents and also antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists.
  • the present invention relates, in particular, to combinations of at least one of the compounds according to the invention with at least one active ingredient which alters the lipid metabolism, an antidiabetic agent, a hypotensive agent and / or an antithrombotic agent.
  • the compounds of the invention may preferably be with one or more
  • the substances which modify the lipid metabolism by way of example and preferably from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, LDL receptor inducers, cholesterol Anti-absorption agents, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, MTP inhibitors, lipase inhibitors, LpL activators, fibrates, niacin, CETP inhibitors, PPAR- ⁇ and / or PPAR- ⁇ agonists, RXR modulators, FXR modulators , LXR modulators, thyroid hormones and / or thyroid mimetics, ATP citrate lyase inhibitors, Lp (a) antagonists, cannabinoid receptor 1 antagonists, leptin receptor agonists, bombesin
  • Receptor agonists histamine receptor agonists and antioxidants / free radical scavengers
  • hypotensive agents by way of example and preferably from the group of calcium antagonists, angiotensin Aue antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers, ECE inhibitors and the vasopeptidase inhibitors;
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • sildenafil sildenafil
  • Vardenafil tadalafil
  • PDE 3 inhibitors such as milrinone
  • Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
  • ABP atrial natriuretic peptide
  • BNP B-type natriuretic peptide
  • CNP C-type natriuretic peptide
  • urodilatin urodilatin
  • Calcium sensitizers such as by way of example and preferably levosimendan
  • NO-independent, but heme-dependent guanylate cyclase stimulators in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
  • Guanylate cyclase NO- and heme-independent activators in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510; • inhibitors of human neutrophil elastase (HNE), such as Sivelestat and DX-890 (Reltran);
  • HNE human neutrophil elastase
  • the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, especially sorafenib, imatinib, Gef ⁇ tinib and erlotinib; and or
  • lipid metabolism-changing active compounds are preferably compounds from the group of HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, lipase inhibitors, thyroid hormones and / or thyroid mimetics, niacin receptor Agonists, CETP inhibitors, PPAR-gamma agonists, PPAR delta agonists, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, antioxidants / radical scavengers, and the cannabinoid receptor 1 antagonists.
  • HMG-CoA reductase inhibitors preferably compounds from the group of HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, lipase inhibitors, thyroid hormones and / or thyroid mimetics, niacin receptor Agonists, CETP inhibitors, PPAR-gam
  • the compounds according to the invention are used in combination with an HMG-Co A reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or Pitavastatin, administered.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or Pitavastatin, administered.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide or JTT-130.
  • an MTP inhibitor such as by way of example and preferably implitapide or JTT-130.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • the compounds according to the invention are administered in combination with a thyroid hormone and / or thyroid mimetic, such as by way of example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3).
  • a thyroid hormone and / or thyroid mimetic such as by way of example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3).
  • the compounds according to the invention are administered in combination with an agonist of the niacin receptor, such as by way of example and preferably niacin, Acipimox, Anatin or Radecol.
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib, JTT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as, by way of example and by way of preference, torcetrapib, JTT-705 or CETP vaccine (Avant).
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as by way of example and preferably pioglitazone or rosiglitazone.
  • the compounds of the invention are administered in combination with a PPAR delta agonist such as, for example and preferably, GW-501516.
  • a PPAR delta agonist such as, for example and preferably, GW-501516.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 AK-105
  • SC-435 SC-635.
  • the compounds according to the invention are administered in combination with an antioxidant / free-radical scavenger, such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
  • an antioxidant / free-radical scavenger such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
  • the compounds according to the invention are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant or SR-147778.
  • Antidiabetic agents are preferably understood as meaning insulin and insulin derivatives as well as orally active hypoglycemic agents.
  • Insulin and insulin derivatives here include both insulins of animal, human or biotechnological origin as well as mixtures thereof.
  • the orally active hypoglycemic agents preferably include sulphonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors and PPAR-gamma agonists.
  • the compounds according to the invention are administered in combination with insulin.
  • the compounds according to the invention are administered in combination with a sulphonylurea, such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
  • a sulphonylurea such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
  • the compounds according to the invention are administered in combination with a biguanide, such as by way of example and preferably metformin.
  • the compounds according to the invention are administered in combination with a meglitinide derivative, such as by way of example and preferably repaglinide or nateglinide.
  • a meglitinide derivative such as by way of example and preferably repaglinide or nateglinide.
  • the compounds according to the invention are administered in combination with a glucosidase inhibitor, such as by way of example and preferably miglitol or acarbose.
  • a glucosidase inhibitor such as by way of example and preferably miglitol or acarbose.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the blood pressure lowering agents are preferably understood as meaning compounds from the group of calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers and diuretics.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably a loop diuretic such as furosemide, bumetanide or torsemide, or a thiazide or thiazide-like diuretic such as chlorothiazide or hydrochlorothiazide.
  • a diuretic such as by way of example and preferably a loop diuretic such as furosemide, bumetanide or torsemide, or a thiazide or thiazide-like diuretic such as chlorothiazide or hydrochlorothiazide.
  • an aldosterone or mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds according to the invention are administered in combination with a vasopressin receptor antagonist such as, by way of example and by way of preference, conivaptan, tolvaptan, lixivaptan or SR-121463.
  • a vasopressin receptor antagonist such as, by way of example and by way of preference, conivaptan, tolvaptan, lixivaptan or SR-121463.
  • the compounds according to the invention are administered in combination with an organic nitrate or NO donor, such as by way of example and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, or in combination with inhaled NO.
  • an organic nitrate or NO donor such as by way of example and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, or in combination with inhaled NO.
  • the compounds according to the invention are administered in combination with a positive inotropically active compound, such as by way of example and preferably cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isopro-nicol, epinephrine, norepinephrine, dopamine or dobutamine.
  • a positive inotropically active compound such as by way of example and preferably cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isopro-nicol, epinephrine, norepinephrine, dopamine or dobutamine.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an angiotensin AE antagonist, such as by way of example and preferably losartan, valsartan, candesartan, embusartan or telmisartan.
  • angiotensin AE antagonist such as by way of example and preferably losartan, valsartan, candesartan, embusartan or telmisartan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, for example and preferably, enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, for example and preferably, enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are used in combination with a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, Caroteneol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucinolol.
  • the compounds according to the invention are administered in combination with an alpha-receptor blocker,
  • the compounds according to the invention are used in combination with an antisympathotonicum, such as by way of example and preferably reserpine, clonidine or alpha-methyl-dopa, or in combination with a potassium channel agonist such as, for example and preferably, minoxidil, diazoxide , Dihydralazine or hydralazine.
  • an antisympathotonicum such as by way of example and preferably reserpine, clonidine or alpha-methyl-dopa
  • a potassium channel agonist such as, for example and preferably, minoxidil, diazoxide , Dihydralazine or hydralazine.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors or anticoagulants.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as by way of example and preferably ximelagarran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as by way of example and preferably ximelagarran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPUb / HIa antagonist, such as by way of example and preferably tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • a vitamin K antagonist such as by way of example and preferably coumarin.
  • Particularly preferred in the context of the present invention are combinations containing at least one of the compounds according to the invention and one or more further active compounds selected from the group consisting of HMG-CoA reductase inhibitors (statins), diuretics, beta-receptor blockers, organic nitrates and NO Donors, ACE inhibitors, angiotensin AH antagonists, aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, platelet aggregation inhibitors and anticoagulants, and their use for the treatment and / or prevention of the aforementioned disorders.
  • statins HMG-CoA reductase inhibitors
  • diuretics such as by way of example and preferably coumarin.
  • beta-receptor blockers such as by way of example and
  • the compounds according to the invention can be used for the treatment and / or prophylaxis of cancers alone or as needed in combination with other anti-tumor agents.
  • the present invention particularly relates to combinations of at least one of the compounds according to the invention with at least one other anti-tumor active ingredient selected from the group consisting of alkylating agents, antimetabolites, plant-derived antitumor agents, active ingredients of hormone therapy, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeted drugs, antibodies, immunoconjugates, interferon and / or immunomodulators, antiangiogenic compounds, antisense RNA and RNA interference, and other anti-tumor drugs.
  • Alkylating agents such as chloromethine N-oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, ⁇ imustin, temozolomide, altretamine, apaciquin, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, mafosfamide and mitolactol;
  • Platinum-coordinated alkylating agents such as, for example, cisplatin, carboplatin, eptaplatin, lobaplatin, ⁇ edaplatin, oxaliplatin and satraplatin;
  • Antimetabolites such as methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone or in combination with leucovorin, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, fludarabine, 5-azacitidine,
  • Capecitabine cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan, ⁇ elarabine, ⁇ olatrexed, ocfosfit, disodium premetrexed, pentostatin, pelitrexole, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, and vinorelbine;
  • hormonal agents such as exemestane, lupron, anastrozole, doxercalciferol, fadrozole, formestan, 11-beta hydroxysteroid dehydrogenase-1 inhibitors, 17-alpha hydroxylase / 17,20 lyase inhibitors such as abiraterone acetate, 5-alpha reductase inhibitors such as finasteride and epristeride, anti-estrogens such as tamoxifen Citrate and fulvestrant, trelstar, toremifene, raloxifene, lasofoxifene, letrozole, anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex and anti-progesterone, and combinations thereof;
  • plant-derived anti-tumor agents such as mitotic inhibitors such as epothilones (sagopilone, ixabepilone and epothilone B), vinblastine, vinflunine, docetaxel, and
  • Cytotoxic topoisomerase inhibitors such as aclarubicin, doxorubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan, topotecan, edotecarin, epimbicin, etoposide, exatecan, germantcan, lurtotecan, mitoxantrone, pirambicin, pixantrone, Rubitecan, Sobuzoxan, Tafluposide, and combinations thereof;
  • Immunological agents exemplified and preferably from the group of interferons such. Interferon alpha, Interferon alpha-2a, Interferon alpha-2b, Interferon beta, Interferon gamma- Ia and interferon gamma-nl, and other immune stimulants such.
  • Immunomodulators such as Krestin, Lentinan, Sizofiran, Picibanil, ProMun and Ubenimex;
  • Antiangiogenic compounds such as, for example, acitretin, aflibercept, angiostatin, aplidine, asentar, axitinib, recentin, bevacizumab, brivanib alaninate, cilengtide, combretastatin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, rebarastat, Removab, Revlimid , Sorafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide,
  • VEGF inhibitors such as sorafenib, DAST, bevacizumab, sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib, pazopanib, and ranibizumab;
  • Antibodies such as trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, orregovomab and alemtuzumab; EGFR (HERI) inhibitors such as cetuximab, panitumumab, vectibix, geftinib, erlotinib and Zactima;
  • HER2 inhibitors such as lapatinib, tratuzumab and pertuzumab;
  • mTOR inhibitors such as temsirolimus, sirolimus / rapamycin and everolimus;
  • CDK inhibitors such as roscovitine and flavopiridol
  • Spindle assembly checkpoint inhibitors and targeted mitotic inhibitors such as PLK inhibitors, Aurora inhibitors (e.g., hesperadine), checkpoint kinase inhibitors and KSP inhibitors;
  • HDAC inhibitors such as Panobinostat, Vorinostat, MS275, Belinostat and LBH589;
  • Proteasome inhibitors such as bortezomib and carfilzomib;
  • Serine / threonine kinase inhibitors such as MEK inhibitors and Raf inhibitors such as sorafenib;
  • Tyrosine kinase inhibitors such as dasatinib, nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, telatinib, imatinib
  • Corticoids e.g. dexamethasone
  • thalidomide or thalidolide analogues eg lenalidomide Bcl-2 protein inhibitors such as Obatoclax, Oblimersen sodium and Gossypol;
  • CD20 receptor antagonists such as rituximab
  • Ribonucleotide reductase inhibitors such as gemcitabine
  • Tumor necrosis apoptosis inducing ligand receptor 1 agonists such as Mapatumumab
  • 5-hydroxytryptamine receptor antagonists such as rEV598, xaliprod, palonosetron hydrochloride, granisetron, zindol and AB-1001;
  • Integrin inhibitors including Alpha5-betal integrin inhibitors. E7820, JSM 6425, Volociximab and Endostatin;
  • Androgen receptor antagonists including e.g. Nandrolone Decanoate, Fluoxymesterone, Android, Prost-Aid, Andromustine, Bicalutamide, Flutamide, Apo-cyproterone, Apo-Flutamide, Chlormadinone Acetate, Androcur, Tabi, Cyproterone Acetate and Nilutamide;
  • aromatase inhibitors such as Anastrozole, letrozole, testolactone, exemestane, amino-glutethimide and formestane;
  • the compounds according to the invention can also be used for the treatment of cancers in conjunction with radiotherapy and / or surgical interventions.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonary, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalants, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers eg, albumin
  • stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odor remedies include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (eg, albumin
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • UV ultraviolet spectrometry v / v volume-to-volume ratio (of a mixture)
  • Method 1 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 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: 50 ° C .; UV detection: 210 nm.
  • Method 2 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2.5 ⁇ MAX-RP 100A 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 -> 0.1 min 90% A -> 3.0 min 5% A -> 4.0 min 5% A - »4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 3 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 100 x 4.6 mm; Eluent A: 1 liter of water + 0.5 ml of 50% formic acid; Eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 10% B ⁇ 7.0 min 95% B ⁇ 9.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min - * 7.0 min 2.0 ml / min ⁇ 9.0 min 2.0 ml / min; UV detection: 210 nm
  • Method 4 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2.5 ⁇ MAX-RP 100A 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 ⁇ 0.1 min 90% A ⁇ 3.0 min 5% A ⁇ * 4.0 min 5% A ⁇ 4.1 min 90% A; Flow: 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • Method 6 Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD l, 9 ⁇ 50 x lmm; 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 - ⁇ 0.1 min 90% A -> 1.5 min 10% A - »2.2 min 10% A; Oven: 50 ° C; Flow: 0.33 ml / min; UV detection: 210 nm.
  • Method 7 Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ 20 x 4 mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 100% A ⁇ 3.0 min 10% A - * 4.0 min 10% A- »4.01 min 100% A (flow 2.5 ml) ⁇ 5.00 min 100% A Oven: 50 ° C., flow: 2 ml / min, UV detection: 210 nm
  • Example 2A 5.00 g (14.4 mmol) of Example 2A were dissolved in 100 ml of abs. DMF submitted. Subsequently, 57.5 ml (28.8 mmol) of isobutylzinc bromide were rapidly added dropwise as a 0.5M solution in THF and 0.831 g (0.719 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. After the onset of reaction (slight).
  • Example 2A 200 mg (0.575 mmol) of Example 2A were initially charged in 7 ml of tetrahydrofuran, and 0.863 ml (1.76 mmol) of lithium isopropylate solution (2M in THF) were added. It was then stirred overnight at room temperature. After removal of the volatile components on a rotary evaporator, the mixture was purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 ⁇ 95: 5). After drying under high vacuum, 172 mg (81% of theory) of the target compound were obtained.
  • preparative HPLC eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 ⁇ 95: 5
  • the aqueous phase was extracted with ethyl acetate. Subsequently, the combined organic phases were washed with aqueous 2M sodium carbonate solution and then with concentrated aqueous sodium chloride solution. After drying with magnesium sulfate, the solvent was removed on a rotary evaporator. The crude product was taken up in 25 ml of diisopropyl ether and dissolved in the heat. The crystallization was then initiated with 3 ml of ⁇ -pentane. The precipitated solid was isolated by filtration and then washed with 2 ml of diisopropyl ether. After drying under high vacuum, 1.40 g (12% of theory) of the target compound were obtained.
  • Example 6A and 60.2 mg (0.391 mmol) of 3-fluoro-4-methylphenylboronic acid were initially charged in 5 ml of dioxane. Then, 1.17 ml (2.34 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 27.4 mg (0.039 mmol) of bis (triphenylphosphine) palladium (II) chloride and 11.9 mg (0.039 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight. After cooling was added with 20 ml of ethyl acetate and 20 ml of water.
  • the aqueous phase was extracted with 10 ml of ethyl acetate.
  • the organic phases were combined and dried with magnesium sulfate.
  • After separation of the volatile components on a rotary evaporator was purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 ⁇ 95: 5). This gave 72 mg (56% of theory) of the target compound.
  • Example 6A 100.0 mg (0.391 mmol) of Example 6A and 60.2 mg (0.391 mmol) of 3,5-difluorophenylboronic acid were initially charged in 5 ml of dioxane. Then, 1.17 ml (2.34 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 27.4 mg (0.039 mmol) of bis (triphenylphosphine) palladium ( ⁇ ) chloride and 11.9 mg (0.039 mmol) of tri-2-tolylphosphine were added. Then stirred overnight at 6O 0 C. After cooling, 20 ml of ethyl acetate and 20 ml of water were added.
  • the aqueous phase was extracted with 10 ml of ethyl acetate.
  • the organic phases were combined and dried with magnesium sulfate.
  • the mixture was purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 ⁇ 95: 5). This gave 90 mg (69% of theory) of the target compound.
  • Example 2A 150.0 mg (0.431 mmol) of Example 2A and 0.055 ml (0.647 mmol) of isopropylamine were initially charged in 3 ml of THF. Then was added and reacted overnight in a closed vessel at 70 0 C with 0.150 ml (1:08 mmol) of triethylamine. After removal of the volatile components on a rotary evaporator, the mixture was purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 ⁇ 95: 5). This gave 95 mg (59% of theory) of the target compound.
  • preparative HPLC eluent: acetonitrile / water with 0.1% formic acid, gradient 20: 80 ⁇ 95: 5
  • Example 2A 150.0 mg (0.431 mmol) of Example 2A and 0.067 ml (0.647 mmol) of N-methylpropan-2-amine were initially charged in 3 ml of THF. Then it was mixed with 0.150 ml (1.08 mmol) of triethylamine and over
  • Example 13A 100.0 mg (0.352 mmol) of Example 13A and 55.6 mg (0.352 mmol) of 3,5-difluorophenylboronic acid were initially charged in 5 ml of dioxane. Then, 1.06 ml (2.11 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred for 10 minutes at room temperature. 24.7 mg (0.035 mmol) of bis (triphenylphosphine) palladium (II) chloride and 10.7 mg (0.035 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight. After cooling, 20 ml of ethyl acetate and 20 ml of water were added.
  • Example 18A and 49.7 mg (0.323 mmol) of 3-fluoro-4-methylphenylboronic acid were initially charged in 4 ml of dioxane. Then, 0.969 ml (1.97 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 22.7 mg (0.032 mmol) of bis (triphenylphosphine) palladium (II) chloride and 9.8 mg (0.032 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight.
  • Example 18A 100.0 mg (0.323 mmol) of Example 18A and 51.0 mg (0.323 mmol) of 3,5-difluorophenylboronic acid were initially charged in 4 ml of dioxane. Then, 0.969 ml (1.97 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 22.7 mg (0.032 mmol) of bis (triphenylphosphine) palladium (II) chloride and 9.8 mg (0.032 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight.
  • Example 18A and 43.9 mg (0.323 mmol) of 4-methylphenylboronic acid were initially charged in 4 ml of dioxane. Then, 0.969 ml (1.97 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 22.7 mg (0.032 mmol) of bis (triphenylphosphine) palladium ( ⁇ ) chloride and 9.8 mg (0.032 mmol) of tri-2-tolylphosphine were added. Then stirred overnight at 6O 0 C. After cooling, 20 ml of ethyl acetate and 20 ml of water were added.
  • Example 18A and 61.3 mg (0.323 mmol) of 4- (trifluoromethyl) phenylboronic acid were initially charged in 4 ml of dioxane. Then, 0.969 ml (1.97 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 22.7 mg (0.032 mmol) of bis (triphenylphosphine) palladium (II) chloride and 9.8 mg (0.032 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight.
  • Example 18A and 43.9 mg (0.323 mmol) of 3-methylphenylboronic acid were initially charged in 4 ml of dioxane. Then, 0.969 ml (1.97 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 22.7 mg (0.032 mmol) of bis (triphenylphosphine) palladium (II) chloride and 9.8 mg (0.032 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight. After cooling, 20 ml of ethyl acetate and 20 ml of water were added.
  • Example IA 3.00 g (10.9 mmol) of Example IA and 1.71 g (10.9 mmol) of 4-chlorophenylboronic acid were initially charged in 100 ml of dioxane. Then, 32.8 ml (65.6 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred for ten minutes at room temperature. There were added 0.768 g (1.10 mmol) of bis (triphenylphosphine) palladium ( ⁇ ) chloride and 0.333 (1.10 mmol) of tri-2-tolylphosphine. Then Ih was stirred at 60 0 C.
  • Example IA 3.00 g (10.9 mmol) of Example IA and 1.49 g (10.9 mmol) of 4-methylphenylboronic acid were initially charged in 100 ml of dioxane. Then, 32.8 ml (65.6 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred for ten minutes at room temperature. There were added 0.768 g (1.10 mmol) of bis (triphenylphosphine) palladium ( ⁇ ) chloride and 0.333 (1.10 mmol) of tri-2-tolylphosphine. Then Ih was stirred at 60 0 C.
  • Example 25A 50.6 mg (0.682 mmol) of 2-methylpropan-1-ol were initially charged in 2 ml of tetrahydrofuran and combined with 27.3 mg (0.682 mmol) of sodium hydride (60% strength in paraffin oil). Subsequently, 150 mg (0.455 mmol) of Example 25A were added as a solution in 2 ml of tetrahydrofuran and stirred for 2 d at reflux temperature. After removal of the volatile components on a rotary evaporator, it was taken up in water and extracted with ethyl acetate (2 ⁇ 10 ml). The combined organic phases were dried with magnesium sulfate.
  • Example 24A 38.6 mg (0.643 mmol) of propan-2-ol were initially charged in 2 ml of tetrahydrofuran and mixed with 25.7 mg (0.643 mmol) of sodium hydride (60% strength in paraffin oil). Subsequently, 150 mg (0.428 mmol) of Example 24A were added as a solution in 2 ml of tetrahydrofuran and stirred for 2d at reflux temperature. After removal of the volatile components on a rotary evaporator, it was taken up in water and extracted with ethyl acetate (2 ⁇ 10 ml). The combined organic phases were dried with magnesium sulfate.
  • Example 24A added as a solution in 2 ml of tetrahydrofuran and stirred for 2d at reflux temperature. After removal of the volatile components on a rotary evaporator, it was taken up in water and extracted with ethyl acetate (2 ⁇ 10 ml). The combined organic phases were dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure, then purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 ⁇ 95: 5). After drying under high vacuum, 52 mg (31% of theory) of the target compound were obtained.
  • preparative HPLC eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 ⁇ 95: 5
  • Example 13A 200.0 mg (0.782 mmol) of Example 13A and 106 mg (0.782 mmol) of 4-methylphenylboronic acid were initially charged in 6 ml of dioxane. Then, 2.35 ml (4.69 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 54.9 mg (0.078 mmol) of bis (triphenylphosphine) palladium (II) chloride and 23.8 mg (0.078 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight. After cooling, 20 ml of ethyl acetate and 20 ml of water were added.
  • Example 13A 200.0 mg (0.782 mmol) of Example 13A and 122 mg (0.782 mmol) of 4-chloro-phenylboronic acid were initially charged in 6 ml of dioxane. Then, 2.35 ml (4.69 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 54.9 mg (0.078 mmol) of bis (triphenylphosphine) palladium (II) chloride and 23.8 mg (0.078 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight. After cooling, 20 ml of ethyl acetate and 20 ml of water were added.
  • Example 17A 1.60 g (5.45 mmol) of Example 17A were initially charged in 12 ml of DMF and treated in portions with 0.262 g (6.54 mmol) of sodium hydride (60% strength in paraffin oil). It was cooled to 0 0 C and then treated with 1.11 g (5.51 mmol) p-Methoxybenzylbromid. Then the ice bath was removed and stirred at RT overnight. The solvent was distilled off and the residue was partitioned between ethyl acetate and water. The organic phase was dried with magnesium sulfate and the solvent was removed by distillation under reduced pressure.
  • Example 33 A 427 mg (1.00 mmol) of Example 33 A were initially charged in 6 ml of acetonitrile. It was cooled in an ice bath and then 3.19 ml (6.39 mmol) of ammonium cyanide (IV) nitrate solution (2M in THF) was added dropwise.
  • IV ammonium cyanide
  • Example 35A 84 mg (0.259 mmol) of Example 35A and 43 mg (0.272 mmol) of 4-chlorophenylboronic acid were initially charged in 4 ml of dioxane. Then, 0.778 ml (1.56 mmol) of a 2M aqueous potassium carbonate solution were added and the mixture was stirred at room temperature for 10 minutes. 18.2 mg (0.026 mmol) of bis (triphenylphosphine) palladium ( ⁇ ) chloride and 7.9 mg (0.026 mmol) of tri-2-tolylphosphine were added. Then it was stirred at 60 0 C overnight. After cooling, 20 ml of ethyl acetate and 20 ml of water were added.
  • the mixture was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). 55 mg (50% of theory) of the target compound were obtained.
  • Example 2A 100 mg (0.288 mmol) of Example 2A and 37 mg (0.431 mmol) cyclopentylamine in 2 ml of 1,2-ethanediol was stirred for 3 days at 120 0 C.
  • the reaction mixture was purified by preparative HPLC without elution (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). 42 mg (37% of theory) of the target compound were obtained.
  • Example 2A 100 mg (0.288 mmol) of Example 2A and 32 mg (0.431 mmol) of diethylamine in 2 ml of 1,2-ethanediol was stirred for 3 days at 120 0 C.
  • the reaction mixture was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10) without further work-up. 32 mg (29% of theory) of the target compound were obtained.
  • Example 2A 100 mg (0.288 mmol) of Example 2A were initially charged under argon atmosphere in 2 ml of DMF. Then, 1.15 ml (0.575 mmol) of isobutylzinc bromide solution (0.5M in THF) was added dropwise. Then 17 mg (0.014 mmol) of tetrakis (triphenylphosphine) palladium (0) were added and stirred at room temperature for 72 h. The reaction mixture was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10) without further work-up. This gave 33 mg (30% of theory) of the target compound.
  • Example 2A 100 mg (0.288 mmol) of Example 2A were dissolved in 2 ml of DMF. Subsequently, 1.15 ml (0.575 mmol) of butylzinc bromide solution (0.5M in THF) and 17 mg (0.014 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. The reaction mixture was stirred at room temperature overnight. Then ethyl acetate / water (1/1) was added, filtered through diatomaceous earth and the organic phase was evaporated to dryness in vacuo. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). 49 mg (46% of theory) of the target compound were obtained.
  • HPLC preparative HPLC
  • Example 2A 50 mg (0.144 mmol) of Example 2A, 15 mg (0.216 mmol) of 1-cyclopropylmethanamine and 37 mg (0.360 mmol) of triethylamine were stirred as a solution in 2 ml of THF at room temperature for 72 h.
  • Example 2A 50 mg (0.144 mmol) of Example 2A, 20 mg (0.216 mmol) of 2-methoxy-N-methylethanamine and 37 mg (0.360 mmol) of triethylamine were stirred in 2 ml of THF at room temperature for 72 h. A reaction control showed incomplete turnover. Therefore, 13 mg (0.144 mmol) of 2-methoxy-N-methylethanamine and 29 mg (0.288 mmol) of triethylamine were added again. The mixture was then stirred at 80 ° C. overnight. For workup, the reaction mixture was adjusted to pH 1 with 1 N hydrochloric acid.
  • the mixture was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). 30 mg (52% of theory) of the target compound were obtained.
  • Example IA 4.0 g (14.60 mmol) of Example IA were initially charged in 80 ml of dioxane. Under argon, 2.31 g (14.60 mmol) of (3,5-difluorophenyl) boronic acid and 43.8 ml (87.60 mmol) of a 2M aqueous potassium carbonate solution were added. It was stirred for 10 min. Subsequently, 1.03 g (1.46 mmol) of bis (triphenylphosphine) palladium ( ⁇ ) chloride and 0.44 g (1.460 mmol) of tri-2-tolylphosphine were added. The reaction mixture was then heated at 60 ° C. overnight.
  • Example 46A 50 mg (0.142 mmol) of Example 46A, 18 mg (0.213 mmol) of cyclopentylamine and 37 mg (0.360 mmol) of triethylamine were stirred in 2 ml of THF at room temperature for 72 h. The reaction control showed only incomplete conversion. Therefore, 12 mg (0.142 mmol) cyclopentylamine and 29 mg (0.284 mmol) of triethylamine are added again and the mixture stirred for a further 36h at 80 0 C. After removal of the volatile components on a rotary evaporator, the residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). 56 mg (99% of theory) of the target compound were obtained.
  • preparative HPLC eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10
  • Example IA 1.0 g (3.649 mmol) of Example IA were initially charged in 11 ml of dioxane. Then 0.70 g (3.649 mmol) of (3,4-dichlorophenyl) boronic acid and 10.9 ml (21,896 mmol) of a 2M aqueous potassium carbonate solution were added under argon. It was stirred for 10 min at room temperature. Then 0.26 g (0.365 mmol) of bis (triphenylphosphine) palladium (II) chloride and 0.11 mg (0.365 mmol) of tri-2-tolylphosphine were added and the reaction mixture Ih at 6O 0 C stirred.
  • Example IA 3.0 g (10,948 mmol) of Example IA was initially charged in 32 ml of dioxane. Then 1.90 g (10.948 mmol) of (4-chloro-3-fluorophenyl) boronic acid and 32.8 ml (65.687 mmol) of a 2M aqueous potassium carbonate solution were added under argon. It was stirred for 10 min. Then, 0.77 g (1.095 mmol) of bis (triphenylphosphine) palladium (II) chloride and 0.33 g (1.095 mmol) of tri-2-tolylphosphine endeavorgefligt. The reaction mixture was then stirred at 60 ° C. for 2 hours.
  • Example 46A 50 mg (0.142 mmol) of Example 46A, 16 mg (0.213 mmol) of diethylamine and 36 mg (0.355 mmol) of triethylamine were stirred in 2 ml THF until overnight at 80 0 C and then for another two days at 6O 0 C.
  • the reaction control showed only incomplete conversion. Therefore, 10 mg (0.142 mmol) of diethylamine and 29 mg (0.248 mmol) of triethylamine are added again and the mixture stirred for a further 36h at 80 0 C.
  • the crude product was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). 21 mg (39% of theory) of the target compound were obtained.
  • Example IA 1.0 g (3.649 mmol) of Example IA were initially charged in 11 ml of dioxane. Then 0.693 g (3.649 mmol) of (4-trifluoromethylphenyl) boronic acid and 10.9 ml (21.896 mmol) of a 2M aqueous potassium carbonate solution were added under argon. It was stirred for 10 min. Then 0.26 g (0.365 mmol) of bis (triphenylphosphine) palladium (II) chloride and 0.11 g (0.365 mmol) of tri-2-tolylphosphine were added. Subsequently, the reaction mixture was Ih stirred at 60 0 C.
  • Example 24A 44 mg (0.440 mmol) of 4-methoxybutan-2-ol and 34 mg (0.857 mmol) of sodium hydride (60% dispersion in mineral oil) were initially charged in 5 ml of tetrahydrofuran. The reaction mixture was Stirred for 30 minutes at room temperature. Subsequently, 100 mg (0.286 mol) of Example 24A were added as a solution in 2 ml of tetrahydrofuran. The mixture was stirred at 80 ° C. overnight. The solvent was removed on a rotary evaporator and the mixture was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). 37 mg (31% of theory) of the target compound were obtained.
  • preparative HPLC eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10
  • Example 54A 1.80 g (7.91 mmol)
  • Example 54A 1.92 g (8.70 mmol)
  • Example 53A and 0.905 ml (15.8 mmol) of acetic acid were taken up in 30 ml of benzene and stirred overnight at reflux on a water separator. After cooling, it was washed with saturated aqueous sodium bicarbonate solution, the aqueous phase was dried with magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by preparative MPLC (Biotage 4OM cartridge, eluent: isohexane / ethyl acetate 9/1). This gave 2.06 g (52% of theory) of the target compound.
  • Example 55A 2.00 g (4.65 mmol) of Example 55A, were taken up in 15 ml of tert-butanol and treated portionwise with 0.626 g (5.58 mmol) of potassium tert-butoxide. It was stirred at room temperature and then cooled in an ice bath. It was acidified with 15 ml of 1N hydrochloric acid and then diluted with 20 ml of water. Then it was extracted with chloroform (3x). The organic phases were combined, dried with magnesium sulfate and the solvent on
  • Example 56A 276 mg (0.719 mmol) of Example 56A and 228 mg (1.007 mmol) of DDQ were taken up in 15 ml of benzene and stirred for 2 h at room temperature. The volatile components were separated on a rotary evaporator and the residue was suspended in a little acetonitrile. The residue was isolated by filtration and taken up again in a little acetonitrile. It was in the Ultrasound bath finely suspended and purified again by filtration. After drying under high vacuum, 264 mg (96% of theory) of the target compound were obtained as solid.
  • Example 57A 90 mg (0.236 mmol) of Example 57A, 19 ⁇ l (0.247 mmol) of 2-propanol and 64.9 mg (0.247 mmol) of triphenylphosphine were initially charged in 3 ml of THF. After 20 min, 4.8 ⁇ l (0.247 mmol) of DIAD were added dropwise. Subsequently, the reaction mixture was reacted at room temperature overnight. The volatile components were separated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 67 mg (67% of theory) of the target compound.
  • preparative HPLC eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10
  • Example IA 1.0 g (3.649 mmol) of Example IA were initially charged in 10 ml of dioxane. Then 0.733 g (3.649 mmol) of 4-bromophenylboronic acid and 10.9 ml (21.896 mmol) of a 2M aqueous potassium carbonate solution were added under argon. It was stirred for 10 min. Then, 0.26 g (0.365 mmol) of bis (triphenylphosphine) palladium ( ⁇ ) chloride and 0.11 g (0.365 mmol) of tri-2-tolylphosphine were added, and the reaction mixture was stirred at 60 ° C overnight. After cooling, the volatile components were separated on a rotary evaporator.
  • Example 6OA 14.60 g (34.6 mmol) of Example 6OA were taken up in 100 ml of tert-butanol and treated portionwise with 4.66 g (41.5 mmol) of potassium tert-butoxide. The mixture was stirred for 2 h at room temperature and then cooled in an ice bath. It was acidified with 120 ml of 1N hydrochloric acid and then diluted with 20 ml of water. Then it was extracted with chloroform (3x). The organic phases were combined, dried with magnesium sulfate and the solvent was removed on a rotary evaporator.
  • Example 61A 6.41 g (18.43 mmol) of Example 61A and 5.89 g (25.81 mmol) of DDQ were taken up in 230 ml of benzene and stirred at room temperature overnight. The volatile components were removed on a rotary evaporator and the residue was suspended in acetonitrile. The residue was isolated by filtration and taken up again in a little acetonitrile. It was finely suspended in an ultrasonic bath and again filtered by filtration. After drying under high vacuum, 3.86 g (96% of theory) of the target compound were obtained.
  • Example 62A 400 mg (1.16 mmol) of Example 62A were initially charged in 0.5 ml of DMF. It was cooled in an ice bath and then added dropwise 2.0 ml of phosphorus oxychloride dropwise. It was then stirred for 3 hours at reflux temperature. After cooling, the volatile components were separated on a rotary evaporator and the residue taken up in dichloromethane. It was washed with water and 2N aqueous sodium carbonate solution. After drying with magnesium sulfate, the solvent was removed on a rotary evaporator and purified by column chromatography on silica gel with dichloromethane. This gave 419 mg (99% of theory) of the target compound.
  • Example 63A and 112 .mu.l (0.803 mmol) of triethylamine were initially charged in 3 ml of THF, with 109 .mu.l (0.803 mmol) of isopropylamine was added and reacted at 40 0 C for 12 h.
  • a DC control showed incomplete turnover. Therefore, it was heated again to 70 0 C for 24 h. It was then suspended in water, extracted with ethyl acetate, dried with magnesium sulfate and the solvent was removed on a rotary evaporator.
  • the crude product was then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 56 mg (45% of theory) of the target compound.
  • Example 65A 8.57 g (24.2 mmol) of Example 65A, were taken up in 90 ml of tert-butanol and added in portions with 3.26 g (29.1 mmol) of potassium tert-butoxide. The mixture was stirred for 2 h at room temperature and then cooled in an ice bath. It was hydrolyzed with 50 ml of water and acidified with 50 ml of 1N hydrochloric acid. Then it was extracted with chloroform (3x). The organic phases were combined, dried with magnesium sulfate and the solvent was removed on a rotary evaporator. This gave 7.07 g (87% of theory) of the target compound in 93% purity (LC-MS).
  • Example 7OA 180 mg (0.617 mmol) of Example 7OA, 38 .mu.l (0.648 mmol) of ethanol and 170 mg (0.648 mmol) of triphenylphosphine were initially charged in 10 ml of THF. After 20 min, 125 ⁇ l (0.648 mmol) DIAD were added dropwise. Subsequently, the reaction mixture was reacted at room temperature overnight. The purification was carried out by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90: 10). This gave 78 mg (38% of theory) of the target compound.
  • Example 7OA 180 mg (0.617 mmol) of Example 7OA, 50 ⁇ l (0.648 mmol) of isopropanol and 170 mg (0.648 mmol) of triphenylphosphine were initially charged in 10 ml of THF. After 20 min, 125 ⁇ l (0.648 mmol) DIAD were added dropwise. Subsequently, the reaction mixture was reacted at room temperature overnight. The purification was carried out by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). 80 mg (39% of theory) of the target compound were thus obtained.
  • preparative HPLC eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10
  • Example 73A 180 mg (0.553 mmol) of Example 73A, 44 ⁇ l (0.581 mmol) of 2-propanol and 152 mg (0.581 mmol) of triphenylphosphine were initially charged in 10 ml of THF. After 20 minutes, 112 ⁇ l (0.581 mmol) DIAD were added dropwise. Subsequently, the reaction mixture was reacted at room temperature overnight. However, a DC control showed insufficient sales. Therefore, another 44 ⁇ l (0.581 mmol) of 2-propanol, 152 mg (0.581 mmol) of triphenylphosphine and 112 ⁇ l (0.581 mmol) of DIAD were added. After 90 min, the reaction mixture was then purified directly by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 152 mg (70% of theory) of the target compound.
  • preparative HPLC eluent: acetonit
  • Example 3 A 2.92 g (7.91 mmol) of Example 3 A were taken up in 50 ml of isopropanol and admixed with 2.21 g (39.5 mmol) of potassium hydroxide. The mixture was then stirred at reflux temperature for three days. After cooling, the volatile components were removed by distillation under reduced pressure. The residue was taken up in water and the resulting mixture acidified with 1N hydrochloric acid. The precipitated product was separated by filtration. This was then washed with water and then with ⁇ -pentane. After drying under high vacuum, 2.39 g (81% of theory) of the target compound were obtained.
  • Example 2 2.15 g (5.81 mmol) of Example 1 were taken up in 20 ml of ethanol and admixed with 5.81 ml (5.81 mmol) of an aqueous IM sodium hydroxide solution. After stirring for one hour at room temperature, the reaction mixture was filtered, the filtrate was concentrated and the residue was dried under high vacuum. This gave 2.17 g (95% of theory) of the target compound.
  • Example 4A 150 mg (0.431 mmol) of Example 4A were taken up in 5 ml of isopropanol and 1.29 ml (1.29 mmol) of an aqueous IM sodium hydroxide solution were added. It was then stirred at reflux temperature overnight. After cooling, the volatile components were removed by distillation under reduced pressure. The residue was taken up in water and the resulting mixture acidified with 1N hydrochloric acid. It was extracted with ethyl acetate, dried with magnesium sulfate and the volatile components were separated on a rotary evaporator. The crude product was purified by preparative HPLC Purified (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5). After drying under high vacuum, 70 mg (45% of theory) of the target compound were obtained.
  • Example 7A 70 mg (5.81 mmol) of Example 7A were taken up in 5 ml of methanol and treated with 0.637 ml (0.637 mmol) of an aqueous IM sodium hydroxide solution. Subsequently, over
  • Example 8A 90 mg (0.270 mmol) of Example 8A were taken up in 4 ml of methanol and admixed with 0.810 ml (0.810 mmol) of an aqueous IM sodium hydroxide solution. It was then 45 min at 14O 0 C in a single-morrow microwave (Emrys Optimizer) implemented. The mixture was concentrated, taken up in 10 ml of water, acidified with 1N hydrochloric acid and the precipitated product was isolated. After drying under high vacuum, 56 mg (65% of theory) of the target compound were obtained.
  • Example 10A 95 mg (0.257 mmol) of Example 10A were taken up in 4 ml of methanol and treated with 0.770 ml (0.770 mmol) of an aqueous IM sodium hydroxide solution. It was then reacted overnight at 70 0 C in a closed vessel. The mixture was concentrated, taken up in 10 ml of water, acidified with 1N hydrochloric acid and the precipitated product was isolated. After drying under high vacuum, 63 mg (69% of theory) of the target compound were obtained.
  • Example I IA 96 mg (0.250 mmol) of Example I IA were taken up in 4 ml of methanol and treated with 0.749 ml (0.749 mmol) of an aqueous IM sodium hydroxide solution. Subsequently, one hour at 120 0 C in a single moc / e microwave (Emrys Optimizer) implemented. The mixture was concentrated, taken up in 10 ml of water and acidified with 1N hydrochloric acid. The water was distilled off under reduced pressure. The final purification is then carried out by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 ⁇ 95: 5). After drying under high vacuum, 16 mg (17% of theory) of the target compound were obtained.
  • preparative HPLC eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 ⁇ 95: 5
  • Example 14A 137 mg (0.416 mmol) of Example 14A were taken up in 8 ml of 2-propanol and 2.00 ml (4,000 mmol) of 2M aqueous potassium hydroxide solution were added. The mixture was then reacted for 2 hours at 180 0 C in a single A / oßfe microwave (Emrys Optimizer). The reaction was concentrated, taken up in 10 ml of water and acidified with 2N hydrochloric acid. It was with ethyl acetate extracted (3x20 ml), the combined organic phases dried with magnesium sulfate and the solvent removed on a rotary evaporator.
  • the crude product was purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 20:80 -> 95: 5). After drying under high vacuum, 77 mg (58% of theory) of the target compound were obtained.

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Abstract

L'invention concerne de nouveaux dérivés de l'acide 6-phénylnicotinique substitué, leur procédé de production, leur utilisation pour le traitement et/ou la prophylaxie de maladies, ainsi que leur utilisation pour la production de médicaments destinés au traitement et/ou la prophylaxie de maladies, de préférence, au traitement et/ou la prophylaxie de maladies cardiovasculaires, en particulier, de dyslipidémies, d'artériosclérose et d'insuffisance cardiaque.
EP08801700A 2007-09-07 2008-08-26 Acides 6-phénylnicotiniques substitués et leur utilisation Withdrawn EP2197846A1 (fr)

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DE102007042754A DE102007042754A1 (de) 2007-09-07 2007-09-07 Substituierte 6-Phenylnikotinsäuren und ihre Verwendung
PCT/EP2008/006969 WO2009033561A1 (fr) 2007-09-07 2008-08-26 Acides 6-phénylnicotiniques substitués et leur utilisation

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US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
TW201215387A (en) 2010-07-05 2012-04-16 Sanofi Aventis Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
TW201221505A (en) 2010-07-05 2012-06-01 Sanofi Sa Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
EP2760862B1 (fr) 2011-09-27 2015-10-21 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US9113629B2 (en) * 2013-03-15 2015-08-25 Dow Agrosciences Llc 4-amino-6-(4-substituted-phenyl)-picolinates and 6-amino-2-(4-substituted-phenyl)-pyrimidine-4-carboxylates and their use as herbicides
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KR20100066545A (ko) 2010-06-17
MX2010002565A (es) 2010-04-30
WO2009033561A8 (fr) 2010-06-10
CA2698471A1 (fr) 2009-03-19
BRPI0816372A2 (pt) 2015-02-24
JP2010538025A (ja) 2010-12-09
PA8794401A1 (es) 2009-07-23
AU2008298021A1 (en) 2009-03-19
UY31310A1 (es) 2009-04-30
NZ583697A (en) 2012-04-27
US20100234432A1 (en) 2010-09-16
US8143411B2 (en) 2012-03-27
WO2009033561A1 (fr) 2009-03-19
TW200914002A (en) 2009-04-01
PE20090954A1 (es) 2009-07-24
DE102007042754A1 (de) 2009-03-12
CL2008002537A1 (es) 2009-03-20

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