EP2158206A1 - Furopyrimidines substituées et leur utilisation - Google Patents

Furopyrimidines substituées et leur utilisation

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Publication number
EP2158206A1
EP2158206A1 EP08758971A EP08758971A EP2158206A1 EP 2158206 A1 EP2158206 A1 EP 2158206A1 EP 08758971 A EP08758971 A EP 08758971A EP 08758971 A EP08758971 A EP 08758971A EP 2158206 A1 EP2158206 A1 EP 2158206A1
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EP
European Patent Office
Prior art keywords
group
formula
substituted
cycloalkenyl
alkyl
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.)
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Application number
EP08758971A
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German (de)
English (en)
Inventor
Thomas Lampe
Raimund Kast
Mario Jeske
Friederike Stoll
Joachim Schuhmacher
Eva-Maria Becker
Hartmut Beck
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Bayer Intellectual Property GmbH
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Bayer Schering Pharma AG
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Publication of EP2158206A1 publication Critical patent/EP2158206A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present application relates to novel, substituted furopyrimidine derivatives, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or Prophylaxis of cardiovascular diseases.
  • Prostacyclin belongs to the family of bioactive prostaglandins, which are derivatives of arachidonic acid.
  • PGI 2 is the major product of arachidonic acid metabolism in endothelial cells and has potent vasodilating and anti-aggregating properties.
  • PGI 2 is the physiological antagonist of thromboxane A 2 (TxA 2 ), a potent vasoconstrictor and platelet aggregation stimulator, thus contributing to the maintenance of vascular homeostasis.
  • TxA 2 thromboxane A 2
  • a reduction in PGI 2 levels is probably responsible for the development of various cardiovascular diseases [Dusting, GJ. et al., Pharmac. Ther. 1990, 48: 323-344; Vane, J. et al., Eur. J. Vase. Endovasc. Surg. 2003, 26: 571-578].
  • PGI 2 After release of arachidonic acid from phospholipids via phospholipases A 2 PGI 2 is synthesized by cyclooxygenases and then by the PGI 2 synthase. PGI 2 is not stored, but released immediately after synthesis, causing its effects locally. PGI 2 is an unstable molecule that is rapidly (half-life about 3 minutes) non-enzymatically rearranged to an inactive metabolite, 6-keto-prostaglandin Fl alpha [Dusting, GJ. et al., Pharmac. Ther. 1990, 48: 323-344].
  • PGI 2 The biological effects of PGI 2 are due to the binding to a membrane-bound receptor, the so-called prostacyclin or IP receptor [Narumiya, S. et al., Physiol. Rev. 1999, 79: 1193-1226].
  • the IP receptor belongs to the G protein-coupled receptors that are characterized by seven transmembrane domains.
  • rat and mouse prostacyclin receptors have also been cloned [Vane, J. et al., Eur. J. Vase. Endovasc. Surg. 2003, 26: 571-578].
  • PGI 2 Although the overall effects of PGI 2 are therapeutically useful, clinical use of PGI 2 is severely limited by its chemical and metabolic instability. More stable PGI 2 analogs such as iloprost [Badesch, DB et al., J. Am. Coli. Cardiol. 2004, 43: 56S-61S] and treprostinil [Chattaraj, SC, Curr. Opion. Invest. Drugs 2002, 3: 582-586] could be made available, but the duration of these compounds is still very short. The substances can also be administered to the patient only via complicated administration routes, for example by continuous infusion, subcutaneously or via repeated inhalations. These routes of administration can also lead to additional side effects, such as infections or pain at the injection site. The use of the only PGI 2 derivative orally available to the patient, beraprost [Barst, RJ. et al., J. Am. Coli. Cardiol. 2003, 41: 2119-2125], again limited by its short duration of action.
  • the compounds described in the present application are chemically and metabolically stable, non-prostanoid activators of the IP receptor, which mimic the biological activity of PGI 2 and can thus be used for the treatment of diseases, in particular of cardiovascular diseases ,
  • the present invention relates to compounds of the general formula (I) - -
  • A is O or NR 4 ,
  • R 4 represents hydrogen, (C r C6) alkyl, (C 3 -C 7) -cycloalkyl or (C 4 -C 7) -cycloalkenyl,
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl
  • alkyl may be substituted with hydroxy or amino
  • L 1 is (C 1 -C 7 ) -alkanediyl, (C 2 -C 7 ) -alkendiyl or a group of the formula * -L IA -VL 1B - **,
  • alkanediyl and alkenediyl may be mono- or disubstituted by fluorine
  • L 1A is (C, -C 5 ) -alkanediyl
  • alkanediyl may be substituted with 1 or 2 substituents independently selected from the group consisting of (C r C 4) -alkyl and (C 1 -Q) -alkoxy,
  • L 1B is a bond or (C r C 3 ) -alkanediyl
  • alkanediyl may be substituted once or twice with fluorine
  • V is O or NR 6 ,
  • R 6 is hydrogen, (C r C6) alkyl or (C 3 -C 7) cycloalkyl,
  • L 2 is a bond or (C 1 -C 4 ) -alkanediyl
  • Q is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, 5- to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl, heterocyclyl, phenyl and heteroaryl can each be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, (C 1 -C 4 ) -alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) Alkoxy, trifluoromethoxy, amino, mono (C 1 -C 4 ) -alkylamino and di- (C 1 -C 4 ) -alkylamino,
  • alkyl having a substituent selected from the group consisting of hydroxy, (C r C 4 ) alkoxy, amino, mono (C r C 4 ) -
  • Alkylamino and di (Ci-C 4 ) alkylamino may be substituted
  • L 3 is (C r C 4 ) -alkanediyl or (C 2 -C 4 ) -alkendiyl
  • alkanediyl may be substituted once or twice with fluorine
  • a methylene group of the alkanediyl group may be exchanged for O or NR 7 , - - in which
  • R 7 is hydrogen, (C r C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • Z is a group of the formula
  • R 8 is hydrogen or (C r C 4) alkyl
  • R 1 is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl may in each case be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, formyl, (Ci-C 6) -alkyl, (C 2 -C 6) - alkenyl, (C 2 -C 4) - alkynyl, (C 3 -C 7) cycloalkyl, (C 4 -C 7) cycloalkenyl, (C r C6) alkoxy, trifluoromethyl,
  • Trifluoromethoxy (Ci-C 6) alkylthio, (Ci-C 6) alkylcarbonyl, amino, mono- (Ci-C 6) - alkylamino, di- (C t -C 6) alkylamino, and (Ci-C 6 ) alkylcarbonylamino,
  • alkyl and alkoxy each having a substituent selected from the group consisting of cyano, hydroxy, (CrQ) alkoxy, (Ci-C 4 ) alkylthio, amino, mono (C r C 4 ) alkylamino and di (Ci C 4 ) -alkylamino may be substituted,
  • R 2 is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, 5- to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, where cycloalkyl, cycloalkenyl, heterocyclyl, phenyl and heteroaryl can each be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, formyl, (C 1 -C 6 ) -alkyl, (C 2 -) C 6) alkenyl, (C 2 -C 4) - alkynyl, (C 3 -C 7) cycloalkyl, (C 4 -C 7) cycloalkenyl, (C r C6) alkoxy, trifluoromethyl, trifluoromethoxy, ( C 1 -C 6) -alkylthio, (C 1 -C
  • alkyl and alkoxy each having a substituent selected from the group consisting of cyano, hydroxy, (Ci-C 4 ) alkoxy, (Ci-C 4 ) alkylthio, amino, mono (C] -C 4 ) alkylamino and may be substituted di (C r C 4) alkylamino,
  • R 1 is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, 5- to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl, heterocyclyl, phenyl and heteroaryl may each be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, formyl, (C r C 6 ) alkyl, (C 2 -C 6 ) Alkenyl, (C 2 -C 4 ) -
  • alkyl and alkoxy each having a substituent selected from the group consisting of cyano, hydroxy, (C r C4) alkoxy, (Ci-Q) alkylthio,
  • Amino, mono- (Ci-C 4) -alkylamino and di- (C] -C4) alkylamino can be substituted
  • R 2 is (C 3 -C 7 ) -cycloalkyl, (C 4 -C 7 ) -cycloalkenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl may in each case be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, formyl, (C r C6) alkyl, (C 2 -C 6) - alkenyl, (C 2 -C 4) - alkynyl, (C 3 -C 7) cycloalkyl, (C 4 -C 7) cycloalkenyl, (C r C6) alkoxy, trifluoromethyl, trifluoromethoxy, (Cj-C 6 ) alkylthio, (Ci-Ce) alkylcarbonyl, amino, mono- (Ci-C 6) - alkylamino, di- (Ci-C 6) alkylamino and (C r C6) alkylcarbonylamino,
  • alkyl and alkoxy each having a substituent selected from
  • R 3 is hydrogen, (C r C4) alkyl or cyclopropyl
  • 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), 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.
  • salts physiologically acceptable salts of the compounds according to the invention are preferred in the context of the present 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, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trisethanolamine, 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 salt
  • 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 of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
  • Z is a group of the formula
  • esters which can be hydrolyzed in physiological media, under the conditions of the biological tests described below, and in particular in vivo enzymatically or chemically to the free carboxylic acids, as the biologically mainly active compounds.
  • esters (C 1 -C 4 ) -alkyl esters in which the alkyl group may be straight-chain or branched are preferred.
  • Particularly preferred are methyl or ethyl esters (see also corresponding definitions of the radical R 8 ).
  • alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms. Preference is given to a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.
  • Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 6 carbon atoms and one or two double bonds. Preference is given to a straight-chain or branched alkenyl radical having 2 to 5 carbon atoms and one double bond.
  • Alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond.
  • alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond.
  • ethynyl n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-one in-l-yl.
  • Alkanediyl in the context of the invention is a linear or branched divalent alkyl radical having 1 to 7 carbon atoms.
  • alkyl radical having 1 to 7 carbon atoms.
  • methylene 1,2-ethylene, ethane-1,1-diyl, 1,3-propylene, propane-1,1-diyl, propane-1,2-diyl, propane-2,2-propylene diyl, 1,4-butylene, butane-1,2-diyl, butane-1,3-diyl and butane-2,3-diyl.
  • Alkenediyl in the context of the invention is a linear or branched divalent alkenyl radical having 2 to 7 carbon atoms and up to 2 double bonds. Examples which may be mentioned by way of example and are preferably: ethene-1, 1-diyl, ethene-1,2-diyl, propene-1,1-diyl, propylene-1,2-diyl, propene-1,3-diyl, but-1-one en-1, 4-diyl, but-1-ene-1,3-diyl, but-2-ene-1, 4-diyl and buta-1,3-dien-1, 4-diyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 carbon atoms.
  • a straight-chain or branched alkoxy radical having 1 to 4 is preferred - -
  • Carbon atoms examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylthio in the context of the invention is a linear or branched alkylthio radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • Alkylcarbonyl in the context of the invention is a linear or branched alkyl radical having 1 to 6 carbon atoms and a carbonyl group attached in position 1.
  • 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 represents 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 Nn-hexyl-N-methylamino.
  • Alkylcarbonylamino in the context of the invention represents an amino group which is linked via a carbonyl group with a linear or branched alkyl substituent having 1 to 6 carbon atoms.
  • alkylcarbonylamino in the context of the invention represents an amino group which is linked via a carbonyl group with a linear or branched alkyl substituent having 1 to 6 carbon atoms.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 7 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkenyl is in the context of the invention for a monocyclic cycloalkyl group having 4 to 7 carbon atoms and a double bond. Examples which may be mentioned by way of example include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Heterocyclyl in the context of the invention is a saturated, monocyclic, heterocyclic radical having 5 to 7 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO 2 , where a nitrogen atom can also form an N-oxide.
  • Preference is given to 5- or 6-membered saturated heterocyclyl radicals having one or two ring heteroatoms from the series N and O.
  • pyrrolidinyl pyrrolinyl
  • pyrazolidinyl tetrahydrofiiranyl
  • piperidinyl piperazinyl
  • tetrahydropyranyl morpholinyl
  • hexahydroazepinyl hexahydro-l
  • 4-diazepinyl 4-diazepinyl.
  • Heteroaryl is in the context of the invention for an aromatic heterocycle (heteroaromatic) with 5 or 6 ring atoms and up to 3 heteroatoms from the series N, O and S, wherein a nitrogen atom can also form an N-oxide.
  • aromatic heterocycle heterocycle
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine, preferably chlorine or fluorine.
  • 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.
  • A is O or NR 4 ,
  • R 4 is hydrogen, (C r C4) alkyl or cyclopropyl
  • R 5 is hydrogen or (C 1 -C 3 ) -alkyl, - 1 - in which alkyl may be substituted by hydroxy or amino,
  • L 1 is (C 3 -C 7 ) -alkanediyl, (C 3 -C 7 ) -alkendiyl or a group of formula * -L 1A -VL 1B - **,
  • alkanediyl and alkenediyl may be mono- or disubstituted by fluorine
  • L 1A is (C r C 3 ) -alkanediyl
  • alkanediyl may be substituted by 1 or 2 substituents independently selected from the group consisting of methyl and ethyl,
  • L 1B is (C 1 -C 3 ) -alkanediyl
  • alkanediyl may be substituted once or twice with fluorine
  • V is O or NR 6 ,
  • R 6 is hydrogen, (C r C 3) alkyl or cyclopropyl
  • L 2 is a bond or (C 1 -C 3 ) -alkanediyl
  • Q is (Q 1 -QO-cycloalkyl, (C 4 -C 6 ) -cycloalkenyl, 5- or 6-membered heterocyclyl or phenyl,
  • cycloalkyl, cycloalkenyl, heterocyclyl and phenyl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, (C r C 3) alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, Methylamino, dimethylamino,
  • L 3 is (C r C 3 ) -alkanediyl, (C 2 -C 3 ) -alkendiyl or a group of the formula --W-CR 9 R 10 - ", - W-CH 2 -CR 9 R 10 - * * or --CH 2 -W -CR 9 R 10 - **,
  • alkanediyl may be substituted once or twice with fluorine
  • the point of attachment to the ring Q means
  • W is O or NR 11 ,
  • R 1 ' is hydrogen, (C 1 -C 3 ) -alkyl or cyclopropyl
  • R 9 is hydrogen or fluorine
  • R 10 is hydrogen or fluorine
  • Z is a group of the formula
  • R 8 is hydrogen, methyl or ethyl
  • R 1 is (C 4 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -cycloalkenyl, 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl, - - wherein cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl may each be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, formyl, (Ci-C 4 ) alkyl, (C 2 -C 4 ) Alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 6 ) cycloalkyl, (C 4 -C 6 ) cycloalkenyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy, (C r C 4 ) -alkylthio, (C 1 -C 4 ) -alkylcarbon
  • R 2 is phenyl or 5- or 6-membered heteroaryl
  • phenyl and heteroaryl can each be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro,
  • R 1 is phenyl or 5- or 6-membered heteroaryl
  • phenyl and heteroaryl can each be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, formyl, (C 1 -C 4 ) -alkyl, (C 2 -C 4 ) -alkenyl, ( C 2 -C 4) -alkynyl, (C 3 -C 6) cycloalkyl, (C 4 -C 6) - cycloalkenyl, (C r C 4) alkoxy, trifluoromethyl, trifluoromethoxy, (Ci-C 4) alkylthio , (C r C4) alkylcarbonyl, amino, mono- (C r C 4) alkylamino, di- (C r C 4) alkylamino, and (Ci-C4) alkylcarbonylamino,
  • R 2 is (C 4 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -cycloalkenyl, 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl may in each case be substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, formyl, (C r C4) alkyl, (C 2 -C 4) - Alkenyl, (C 2 -C 4 ) -
  • R 3 is hydrogen or (C r C 3 ) -alkyl
  • A is O or NH
  • R 5 is hydrogen, methyl or ethyl
  • L 1 is (C 3 -C 7 ) -alkanediyl, (C 3 -C 7 ) -alkendiyl or a group of formula * -L 1A -VL 1B - **,
  • L 1A is (C, -C 3 ) -alkanediyl
  • alkanediyl may be substituted by 1 or 2 substituents independently selected from the group consisting of methyl and ethyl,
  • L 1B is (C, -C 3 ) -alkanediyl
  • V is O or N-CH 3 ,
  • L 2 is a bond, methylene, ethane-1, 1-diyl or ethane-1, 2-diyl,
  • Q is cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or phenyl,
  • cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl and phenyl may each be substituted by 1 or 2 substituents independently selected from the group consisting of fluoro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy,
  • L 3 is (QC 3 ) alkanediyl or a group of the formula "-W-CH 2 - ** or
  • the point of attachment to the ring Q means
  • W is O or NR 11 ,
  • R 11 is hydrogen or (C 1 -C 3 ) -alkyl
  • R 1 is (C 4 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -cycloalkenyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl and heteroaryl groups may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, formyl, (C r C4) alkyl, (C 2 -C 4) - Alkenyl, (C r C 4 ) alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 2 is phenyl
  • phenyl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, formyl, (Ci-C 4) alkyl, (C 2 -C 4) alkenyl, (C r C 4 ) Alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 1 is phenyl
  • phenyl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, cyano, formyl, (C r C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C] -C 4 ) alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 2 is (C 4 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -cycloalkenyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl and heteroaryl each may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, formyl, (C r C4) alkyl, (C 2 -C 4) alkenyl, (C r C 4) alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 3 is hydrogen or methyl
  • A is O or NH
  • R 5 is hydrogen, methyl or ethyl
  • L 1 is (C 3 -C 7 ) -alkanediyl, (C 3 -C 7 ) -alkendiyl or a group of the formula
  • L 1A is (C, -C 3 ) -alkanediyl
  • L 1B is (C 1 -C 3 ) -alkanediyl
  • V is O or N-CH 3 ,
  • L 2 is a bond, methylene, ethane-1, 1-diyl or ethane-1, 2-diyl,
  • Q is cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, pyrrolodinyl,
  • cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, pyrrolodinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl and phenyl may each be substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy,
  • L 3 is (C r C3) -alkanediyl or a group of formula "-W-CH 2 - ** 2 -CH 2 or-CH --W - ** is,
  • the point of attachment to the ring Q means
  • W is O or NR 11 ,
  • R 11 is hydrogen or (C r C 3 ) -alkyl
  • Z is a group of the formula
  • R 1 is (C 4 -C 6 ) -cycloalkyl, (Q-Co ⁇ cycloalkenyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl and heteroaryl each may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, formyl, (C r C4) alkyl, (C 2 -C 4) alkenyl, (C 1 -C 4 ) -alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 2 is phenyl, - - where phenyl can be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, formyl, (Ci-C 4) alkyl, (C 2 -C 4) alkenyl, (Ci- C 4 ) alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 1 is phenyl
  • phenyl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, formyl, (Ci-C 4) alkyl, (C 2 -C 4) alkenyl, (C r C 4 ) Alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 2 is (C 4 -C 6 ) -cycloalkyl, (C 4 -C 6 ) -cycloalkenyl or 5- or 6-membered heteroaryl,
  • cycloalkyl, cycloalkenyl and heteroaryl each may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, formyl, (C r C4) alkyl, (C 2 -C 4) alkenyl, (C r C 4) alkoxy, trifluoromethyl and trifluoromethoxy,
  • R 3 is hydrogen or methyl
  • A is O or NH
  • R 5 is hydrogen or methyl
  • L 1 is butan-1, 4-diyl or pentane-1, 5-diyl,
  • L 2 is a bond or methylene
  • Q is cyclopentyl, cyclohexyl or phenyl
  • L 3 represents methylene, ethane-1, 2-diyl, propane-1,3-diyl or a group of the formula: -O-CH 2 -> or -O-CH 2 -CH 2 -**,
  • the point of attachment to the ring Q means
  • Z is a group of the formula
  • R 1 is cyclopent-1-en-1-yl, cyclohexene-1-en-1-yl, thienyl or pyridyl,
  • cyclopent-1-en-1-yl and cyclohexene-1-en-1-yl may each be easily substituted with fluorine
  • thienyl and pyridyl may each be substituted with one substituent selected from the group consisting of fluorine, chlorine, methyl and trifluoromethyl,
  • R 2 is phenyl, - - wherein phenyl may be substituted by a substituent selected from the group consisting of methyl, ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy,
  • R 1 is phenyl
  • Chlorine, methyl, trifluoromethyl, methoxy and trifluoromethoxy may be substituted
  • R 2 is cyclopent-1-en-1-yl, cyclohexene-1-en-1-yl or pyridyl,
  • cyclopent-1-en-1-yl and cyclohexene-1-en-1-yl may each be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl and methoxy,
  • pyridyl may be substituted with one substituent selected from the group consisting of methyl, ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy,
  • R 3 is hydrogen
  • R 1 is cyclopent-1-en-1-yl, cyclohexene-1-en-1-yl, thienyl or pyridyl,
  • cyclopent-1-en-1-yl and cyclohexene-1-en-1-yl may each be easily substituted with fluorine
  • thienyl and pyridyl may each be substituted with one substituent selected from the group consisting of fluorine, chlorine, methyl and trifluoromethyl, - - and
  • R 2 is phenyl
  • phenyl may be substituted with a substituent selected from the group consisting of methyl, ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy,
  • R 1 is phenyl
  • phenyl may be substituted with one substituent selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and trifluoromethoxy,
  • R 2 is cyclopent-1-ene-1-yl, cyclohexene-1-ene-1-yl or pyridy 1,
  • cyclopent-1-en-1-yl and cyclohexene-1-en-1-yl may each be substituted with one substituent selected from the group consisting of methyl, ethyl, trifluoromethyl and methoxy,
  • Ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy can be substituted.
  • L 2 is a bond or methylene, - -
  • Q is cyclopentyl, cyclohexyl or phenyl
  • L 3 represents methylene, ethane-1, 2-diyl, propane-1,3-diyl or a group of the formula: -O-CH 2 -> or -O-CH 2 -CH 2 -**,
  • the point of attachment to the ring Q means
  • R 5 is hydrogen, methyl or ethyl
  • L 1 is (C 3 -C 7 ) -alkanediyl, (C 3 -C 7 ) -alkendiyl or a group of formula * -L 1A -VL 1B - **,
  • L 1A is (C, -C 3 ) -alkanediyl
  • alkanediyl may be substituted by 1 or 2 substituents independently selected from the group consisting of methyl and ethyl, L 1B is (C 1 -C 3 ) -alkanediyl,
  • V is O or N-CH 3 .
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, in which Z is -COOH, which comprises reacting either
  • R 1A is (C 4 -C 7 ) -cycloalkenyl, 5- or 6-membered heteroaryl or phenyl,
  • X 1 represents a leaving group such as, for example, halogen, in particular chlorine,
  • Z 1 is cyano or a group of the formula COOR 8A ,
  • R 8A represents (C r C4) alkyl
  • R is (C 4 -C 7 ) -cycloalkenyl or 5- or 6-membered heteroaryl
  • R 11 is hydrogen or both radicals R 11 together form a -C (CH 3 ) 2 -C (CH 3 ) 2 - bridge,
  • R is (C 4 -C 7 ) -cycloalkenyl, 5- or 6-membered heteroaryl or phenyl,
  • R 1B is (C 4 -C 7 ) -cycloalkenyl or 5- or 6-membered heteroaryl
  • R is 5- or 6-membered heteroaryl
  • R is 5- or 6-membered heteroaryl
  • X is a leaving group such as halogen or
  • Trifluoromethanesulfonyloxy in particular for bromine or
  • Inert solvents for process steps (HA) + (III) ⁇ (IV-A) and (HB) + (III) ⁇ (IV-B) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF ), Dimethylsulfoxide (DMSO), NN-dimethylpropyleneure
  • process steps (II-A) + (III) ⁇ (IV-A) and (H-B) + (III) ⁇ (IV-B) can also be carried out without a solvent.
  • Suitable bases for the process steps (H-A) + (IH) ⁇ (IV-A) and (H-B) + ( ⁇ i) ⁇ (IV-B) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or Potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine or pyridine.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • the reactions (II-A) + (IH) -> (FV-A) and (HB) + (III) ⁇ (IV-B) can also be carried out in a two-phase mixture consisting of an aqueous alkali metal hydroxide - Solution as a base and one of the above hydrocarbons or halogenated hydrocarbons as a further solvent, using a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide are performed.
  • a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide are performed.
  • the bromination in the process steps (FV-A) - »(VA) or (FV-B) -> (VB) is preferably in a halohydrocarbon solvent, in particular in carbon tetrachloride, in a temperature range from +50 0 C to +100 0 C performed.
  • Suitable brominating agents are elemental bromine and in particular N-bromosuccinimide ( ⁇ BS), optionally with addition of ⁇ , ⁇ '-azobis (isobutyronitrile) (AFB ⁇ ) as initiator.
  • Inert solvents for process steps (VA) + (VI-A) ⁇ (VII-A), (VB) + (VI-B) -> (VII-B), (VE) + (VI-E) ⁇ (VII
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butyl
  • Petroleum fractions or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ MP), pyridine, acetonitrile or also
  • VE As bases for the process steps (VA) + (VI-A) ⁇ (VII-A), (VB) + (VI-B) ⁇ (VII-B), (VE) + (VI-E) ⁇ (VII- C) and (VA) + (bis (pinacolato) -diboron) ⁇ (VE) are customary inorganic bases.
  • alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide
  • alkali hydrogen carbonates such as sodium or potassium bicarbonate
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
  • alkali hydrogen phosphates such as disodium or dipotassium hydrogencarbonate.
  • phosphate Preferably, sodium or potassium carbonate is used.
  • the reactions (VA) + (VI-A) ⁇ (VII-A), (VB) + (VI-B) ⁇ (VII-B), (VE) + (VI-E) ⁇ (VII-C) and (VA) + (bis (pinacolato) -diboron) -> (VE) are generally carried out in a temperature range from + 2O 0 C to +150 0 C, preferably at + 5O 0 C to + 100 0 C.
  • Inert solvents for process steps (VA) + (VI-C) ⁇ (VII-C) and (VB) + (VI-D) ⁇ (VII-D) are, for example, ethers, such as dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, NN-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ MP), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to toluene.
  • palladium (O) - or palladium (I ⁇ ) compounds especially bis (dibenzylideneacetone) palladium (0), tetrakis (triphenylphosphine) palladium (0), palladium (H) acetate, bis (triphenylphosphine) palladium (II) chloride suitable [see also: V. Farina, V. Krishnamurthy, WY. Scott in: The Silent Reaction, 1998, J. Wiley and Sons, New York].
  • the reactions (VA) + (VI-C) ⁇ (VII-C) and (VB) + (VI-D) ⁇ (VU-O) are generally in a temperature range of +60 0 C to + 15O 0 C, preferably carried out at +100 0 C to +130 0 C.
  • the hydrolysis of the cyano or ester group Z 1 of the compounds (VII-A), (VII-B), (VII-C) or (VII-D) to give compounds of the formula (1-1) is carried out according to customary methods Methods by treating the esters or nitriles in inert solvents with acids or bases, wherein in the latter, the initially formed salts are converted by treatment with acid in the free carboxylic acids. In the case of the tert-butyl ester ester cleavage is preferably carried out with acids.
  • Suitable inert solvents for these reactions are water or the organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
  • Suitable bases are the customary inorganic bases. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium 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 the tert-butyl esters and hydrochloric acid in the case of the methyl esters.
  • the Esterspaltung is generally carried out in a temperature range of 0 0 C to +100 0 C, forthcoming Trains t +0 at 0 C to +50 0 C.
  • the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
  • Inert solvents for this reaction 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 dimethyl sulfoxide, dimethylformamide, N, N'-dimethylpropyleneurea (DMPU). or N-methylpyrrolidone ( ⁇ MP). It is likewise possible to use mixtures of the solvents mentioned.
  • DMPU dimethylformamide
  • ⁇ MP N-methylpyrrolidone
  • sodium azide in the presence of ammonium chloride or trimethylsilyl azide is suitable as an azide reagent.
  • the latter reaction can advantageously be carried out in the presence of a catalyst.
  • Compounds such as di-n-butyltin oxide, trimethylaluminum or zinc bromide are particularly suitable for this purpose.
  • trimethylsilyl azide is used in combination with di-n-butyltin oxide.
  • the reaction is generally carried out in a temperature range from + 5O 0 C to + 15O 0 C, preferably at + 60 0 C to +110 0 C.
  • the reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.
  • phosgene or a phosgene equivalent such as NN'-carbonyldiimidazole.
  • Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether are suitable as inert solvents for the first step of this reaction sequence. It is also possible to use mixtures of these solvents. Preferably, a mixture of methanol and tetrahydrofuran is used.
  • the second reaction step is preferably carried out in an ether, in particular in tetrahydrofuran.
  • the reactions are generally carried out in a temperature range from 0 C to +70 0 C under atmospheric pressure.
  • X is a leaving group such as halogen, mesylate or tosylate,
  • n is the number 0 or 1
  • A, L 2 , Q, W, Z 1 , R 1 , R 2 , R 3 , R 9 , R 10 and m are each as defined above, - - transferred and then further implemented according to the method described above.
  • Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular those listed under R 1 and R 2 , starting from the compounds of the formula (I) obtained by the above methods.
  • transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of Carbonamides, as well as introduction and removal of temporary protecting groups.
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention are chemically and metabolically stable, non-prostanoid activators of the LP receptor.
  • cardiovascular diseases such as stable and unstable angina pectoris, hypertension and heart failure, pulmonary hypertension, for the prophylaxis and / or treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transitori and for inhibiting restenosis such as thrombolytic therapies, percutaneous transluminal angioplasties (PTA), coronary angioplasties (PTCA) and bypass.
  • PTA percutaneous transluminal angioplasties
  • PTCA coronary angioplasties
  • the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary hypertension (PH) including its various forms.
  • the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension (PAH) and its sub-forms, such as idiopathic, familial and, for example, with portal hypertension, fibrotic diseases, HIV infection or improper Drug or toxin-associated pulmonary arterial hypertension.
  • PAH pulmonary arterial hypertension
  • the compounds of the invention may also be used for the treatment and / or prophylaxis of other forms of pulmonary hypertension.
  • they can be used, for example, for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases and in left-sided heart valve diseases.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension in chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness and pulmonary developmental disorders.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension due to chronic thrombotic and / or embolic diseases, such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism.
  • the compounds according to the invention can be used for the treatment and / or prophylaxis of pulmonary hypertension in connection with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis as well as pulmonary hypertension caused by external vascular compression (lymph node, tumor, fibrosing mediastinitis).
  • the compounds according to the invention can also be used for the treatment and / or prophylaxis of peripheral and cardiac vascular diseases, of peripheral occlusive diseases (PAOD, PVD) as well as of peripheral circulatory disorders.
  • PAOD peripheral occlusive diseases
  • PVD peripheral occlusive diseases
  • the compounds of the present invention may be useful in the treatment of arteriosclerosis, hepatitis, asthmatic diseases, chronic obstructive pulmonary disease (COPD), pulmonary edema, fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF) and ARDS, inflammatory vascular diseases such as scleroderma and lupus erythematosus, renal failure, arthritis and osteoporosis and for the prophylaxis and / or treatment of cancer, in particular of metastatic tumors.
  • COPD chronic obstructive pulmonary disease
  • pulmonary edema fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF) and ARDS
  • inflammatory vascular diseases such as scleroderma and lupus erythematosus, renal failure, arthritis and osteoporosis and for the prophylaxis and / or treatment of cancer, in particular of metastatic tumors.
  • the compounds of the invention may also be used as an adjunct to the preservative medium of an organ transplant, such as e.g. in kidneys, lungs, heart or islet cells.
  • Another object of the present invention is the use of 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 angina pectoris, pulmonary hypertension, thromboembolic disorders and peripheral occlusive diseases.
  • 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 may be mentioned by way of example and preferably:
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • NO-independent, but heme-dependent guanylate cyclase simulators 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;
  • HNE human neutrophil elastase
  • the signal transduction cascade inhibiting compounds for example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors;
  • VPAC receptors such as by way of example and preferably the vasoactive intestinal polypeptide
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or prof ⁇ brinolytic substances;
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor B-relaxer, mineralocorticoid receptor Antagonists, Rho kinase inhibitors and diuretics; and or
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.
  • cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid
  • the compounds according to the invention are used in combination with a kinase inhibitor, such as, for example and preferably, canertinib, - -
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / HIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / HIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with 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.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptors B loose, mineralocorticoid receptor Tor antagonists, Rho kinase inhibitors and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist, such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as, by way of example and by way of preference, spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as, by way of example and by way of preference, spironolactone or eplerenone.
  • the compounds according to the invention are administered in combination with a rho-kinase inhibitor, such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.
  • a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.
  • a diuretic such as by way of example and preferably furosemide.
  • the fat metabolism modifying agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid rea
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds 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 D3AT
  • 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 a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating the application forms, which contain compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (non-coated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), in which Oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets non-coated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention
  • Oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emul
  • 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 medicines including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous 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 dodecy
  • 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.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; 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.
  • Device Type MS Waters ZQ
  • Device type HPLC Waters Alliance 2795
  • 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
  • Flow 2 ml / min
  • Oven 40 ° C
  • UV detection 210 nm.
  • 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
  • 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.
  • Instrument Micromass GCT, GC6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 7O 0 C; Inlet: 250 ° C; Gradient: 70 0 C, 30 ° C / min ⁇ 310 0 C (3 min hold).
  • the crude product is purified by chromatography on silica gel (eluent: dichloromethane).
  • the product is stirred for further purification in methanol, filtered off with suction and dried under high vacuum. 32 g of the target product are obtained (55.5% of theory).
  • Solution A 10.71 g (267.7 mmol) of 60% sodium hydride are dissolved in 150 ml of abs. THF was suspended and treated dropwise with cooling with 43.3 ml (276.7 mmol) .P.P-Dimethylphosphonoessigklare- tert-butyl ester. The mixture is stirred at RT, after about 30 min, a solution is formed.
  • aqueous phase is re-extracted with ethyl acetate.
  • organic phases wash with saturated sodium chloride solution, dry over magnesium sulfate and concentrate in vacuo.
  • the residue is purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1). This gives 32.2 g (90.1% of theory) of the target product which contains small amounts of the cis isomer.
  • the reaction mixture is diluted with dichloromethane, washed with ammonium chloride solution and saturated sodium chloride solution, the organic phase is dried over sodium sulfate, concentrated on a rotary evaporator.
  • the crude product is chromatographed on silica gel (dichloromethane then ethyl acetate). 155 mg (25% of theory) of the title compound are obtained.
  • reaction solution After cooling to room temperature, the reaction solution is washed successively rapidly with 250 ml of ice water, twice 250 ml of cold 20% sodium hydroxide solution, 250 ml of ice water, 250 ml of saturated sodium chloride solution, 1 N hydrochloric acid and 250 ml of ice water.
  • the organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. 6.3 g (59% of theory) of the title compound are obtained.
  • the mixture is stirred 10 min at -1O 0 C, the reaction mixture was slowly warmed to RT and stirred for 2.5 h at this temperature.
  • the reaction mixture is added water, made acid to neutrality with 1 M and extracted with dichloromethane. the organic phase is dried over sodium sulfate The residue is chromatographed on silica gel with a gradient of cyclohexane and ethyl acetate 7/1 ⁇ 5/1, giving 4.3 g (53% of theory) of the target compound.
  • the reaction mixture is diluted with dichloromethane, washed with water and saturated sodium chloride solution, and the aqueous phase is extracted with dichloromethane.
  • the combined organic phases are over sodium sulfate - - Dried and concentrated on a rotary evaporator.
  • the residue is dried in vacuo and chromatographed on silica gel with an eluent of cyclohexane and ethyl acetate 10/1. 691 mg (60% of theory) of target compound are obtained.
  • the reaction mixture is washed three times with water and once with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo.
  • the crude product is purified by chromatography on silica gel (gradient cyclohexane / dichloromethane 2: 1 to 1: 2). 9.3 g of target product are obtained (73.6% of theory).
  • reaction mixture is diluted with dichloromethane, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. After drying in a high vacuum, 21 mg (33% of theory) of the title compound are obtained.

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Abstract

La présente invention concerne de nouveaux dérivés furopyrimidiques substitués, des procédés de production desdits dérivés, leur utilisation dans le traitement et/ou la prophylaxie de maladies ainsi que leur utilisation dans la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies, notamment au traitement et/ou à la prophylaxie de maladies cardiovasculaires.
EP08758971A 2007-06-16 2008-06-03 Furopyrimidines substituées et leur utilisation Withdrawn EP2158206A1 (fr)

Applications Claiming Priority (2)

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DE102007027799A DE102007027799A1 (de) 2007-06-16 2007-06-16 Substituierte Furopyrimidine und ihre Verwendung
PCT/EP2008/004407 WO2008155016A1 (fr) 2007-06-16 2008-06-03 Furopyrimidines substituées et leur utilisation

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CA (1) CA2690527A1 (fr)
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WO2008155016A1 (fr) 2008-12-24
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CA2690527A1 (fr) 2008-12-24
DE102007027799A1 (de) 2008-12-18

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